TDP-43 Proteinopathy Research Articles

RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.

TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient.

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.

TDP-43 pathology is associated with increased tau burdens and seeding

BackgroundMost Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD.MethodsIn this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice.ResultsWe found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed.ConclusionsOur findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients.

TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains

BackgroundInclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.MethodsTo investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.ResultsWe detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.ConclusionsOverall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration.

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer's disease patients.

TDP-43 proteinopathy in Alzheimer's disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism. We have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments. TDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs. TTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease.

LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Neuropathological outcomes of traumatic brain injury and alcohol use in males and females: studies using preclinical rodent and clinical human specimens.

Traumatic brain injury (TBI) and alcohol misuse are inextricably linked and can increase the risk for developing neurodegenerative diseases, particularly in military veterans and contact sport athletes. Proteinopathy (defects in protein degradation) is considered an underlying factor in neurodegenerative diseases. However, whether it contributes to TBI/alcohol-mediated neurodegeneration is unexplored. Our recent studies have identified ISGylation, a conjugated form of ISG15 (Interferon-Stimulated Gene 15) and inducer of proteinopathy, as a potential mechanistic link underlying TBI-mediated neurodegeneration and proteinopathy in veterans. In the current study, a rat model of combined TBI and alcohol use was utilized to investigate the same relationship. Here, we report sustained induction of Interferon β (IFNβ), changes in TAR DNA Binding 43 (TDP-43) ISGylation levels, TDP-43 proteinopathy (C-terminal fragmentation (CTF)), and neurodegeneration in the ventral horns of the lumbar spinal cords (LSCs) and/or motor cortices (MCs) of female rats post-TBI in a time-dependent manner. In males, these findings mostly remained non-significant, though moderate alcohol use appears to decrease neurodegeneration in males (but not females) post-TBI. We, however, do not claim that moderate alcohol consumption is beneficial for preventing TBI-mediated neurodegeneration. We have previously demonstrated that ISGylation is increased in the LSCs of veterans with TBI/ALS (Amyotrophic Lateral Sclerosis). Here, we show increased ISGylation of TDP-43 in the LSCs of TBI/ALS-afflicted female veterans compared to male veterans. Knowing that ISGylation induces proteinopathy, we suggest targeting ISGylation may prevent proteinopathy-mediated neurodegeneration post-TBI, particularly in women, however, causal studies are required to confirm this claim.

Different Chronic Stress Paradigms Converge on Endogenous TDP43 Cleavage and Aggregation

The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response.

Targeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo

Cytoplasmic aggregation and concomitant nuclear clearance of the RNA-binding protein TDP-43 are found in ~ 90% of cases of amyotrophic lateral sclerosis and ~ 45% of patients living with frontotemporal lobar degeneration, but no disease-modifying therapy is available. Antibody therapy targeting other aggregating proteins associated with neurodegenerative disorders has shown beneficial effects in animal models and clinical trials. The most effective epitopes for safe antibody therapy targeting TDP-43 are unknown. Here, we identified safe and effective epitopes in TDP-43 for active and potential future passive immunotherapy. We prescreened 15 peptide antigens covering all regions of TDP-43 to identify the most immunogenic epitopes and to raise novel monoclonal antibodies in wild-type mice. Most peptides induced a considerable antibody response and no antigen triggered obvious side effects. Thus, we immunized mice with rapidly progressing TDP-43 proteinopathy (“rNLS8” model) with the nine most immunogenic peptides in five pools prior to TDP-43ΔNLS transgene induction. Strikingly, combined administration of two N-terminal peptides induced genetic background-specific sudden lethality in several mice and was therefore discontinued. Despite a strong antibody response, no TDP-43 peptide prevented the rapid body weight loss or reduced phospho-TDP-43 levels as well as the profound astrogliosis and microgliosis in rNLS8 mice. However, immunization with a C-terminal peptide containing the disease-associated phospho-serines 409/410 significantly lowered serum neurofilament light chain levels, indicative of reduced neuroaxonal damage. Transcriptomic profiling showed a pronounced neuroinflammatory signature (IL-1β, TNF-α, NfκB) in rNLS8 mice and suggested modest benefits of immunization targeting the glycine-rich region. Several novel monoclonal antibodies targeting the glycine-rich domain potently reduced phase separation and aggregation of TDP-43 in vitro and prevented cellular uptake of preformed aggregates. Our unbiased screen suggests that targeting the RRM2 domain and the C-terminal region of TDP-43 by active or passive immunization may be beneficial in TDP-43 proteinopathies by inhibiting cardinal processes of disease progression.Graphical

Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells.

The centrosome, as the main microtubule organizing centre, plays key roles in cell polarity, genome stability and ciliogenesis. The recent identification of ribosomes, RNA-binding proteins and transcripts at the centrosome suggests local protein synthesis. In this context, we hypothesized that TDP-43, a highly conserved RNA binding protein involved in the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, could be enriched at this organelle. Using dedicated high magnification sub-diffraction microscopy on human cells, we discovered a novel localization of TDP-43 at the centrosome during all phases of the cell cycle. These results were confirmed on purified centrosomes by western blot and immunofluorescence microscopy. In addition, the co-localization of TDP-43 and pericentrin suggested a pericentriolar enrichment of the protein, leading us to hypothesize that TDP-43 might interact with local mRNAs and proteins. Supporting this hypothesis, we found four conserved centrosomal mRNAs and 16 centrosomal proteins identified as direct TDP-43 interactors. More strikingly, all the 16 proteins are implicated in the pathophysiology of TDP-43 proteinopathies, suggesting that TDP-43 dysfunction in this organelle contributes to neurodegeneration. This first description of TDP-43 centrosomal enrichment paves the way for a more comprehensive understanding of TDP-43 physiology and pathology.

Patterns of TDP-43 Deposition in Brains with LRRK2 G2019S Mutations.

To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation. LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carriers. Twelve brains with LRRK2 G2019S mutations were available for study from the New York Brain Bank at Columbia University; 11 of them had samples available for TDP-43 immunostaining. Clinical, demographic, and pathological data are reported for 11 brains with a LRRK2 G2019S mutation and compared to 11 brains without GBA1 or LRRK2 G2019S mutations with a pathologic diagnosis of Parkinson's disease (PD) or diffuse Lewy body disease. They were frequency matched by age, gender, parkinsonism age of onset, and disease duration. TDP-43 aggregates were present in 73% (n = 8) of brains with a LRRK2 mutation and 18% (n = 2) of brains without a LRRK2 mutation (P = 0.03). In one brain with a LRRK2 mutation, TDP-43 proteinopathy was the primary neuropathological change. Extranuclear TDP-43 aggregates are observed with greater frequency in LRRK2 G2019S autopsies compared to PD cases without a LRRK2 G2019S mutation. The association between LRRK2 and TDP-43 should be further explored. © 2023 International Parkinson and Movement Disorder Society.

Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology.

Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology.

Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases

BackgroundAutosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.ResultsTo test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.ConclusionsTogether, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

RACK1 Knockdown is a Potential Therapeutic Target in ALS and FTLD-TDP (P1-6.003)

<h3>Objective:</h3> To test if RACK1 knockdown in models of TDP-43 proteinopathy might be safe and effective. <h3>Background:</h3> The Receptor of Activated C-Kinase 1 (RACK1) is a ribosomal protein that co-aggregates with pathogenic TDP-43 cytoplasmic inclusions characteristic of ALS and FTLD-TDP, participating in consolidation of TDP-43 aggregation and impaired global protein translation. <h3>Design/Methods:</h3> TDP-43 proteinopathy was modeled by transfection of misfolding HA-tagged dNLS-TDP-43 in HEK293T cells, in which morphology and localization of cytoplasmic aggregates were detected by HA-reactive antibodies, and global protein translation was measured by Surface Sensing of Translation (SUnSET). Drosophila melanogaster expression system (UAS-Gal4) was used to target expression of hTDP-43^WT or hTDP-43^Q331K to retinal or motor neurons. <h3>Results:</h3> No detectable changes in HEK293T cell morphology or viability were generated by siRNA knockdown of endogenous human RACK1. In cells transfected with dNLS-TDP-43, RACK1 knockdown significantly reduced average aggregate area and average aggregate size per transfected cell, surprisingly accompanied by significantly increased nuclear localization of this TDP-43 nuclear localization mutant. RACK1 knockdown also restored global translational suppression induced by dNLS-TDP-43. In D. melanogaster flies expressing hTDP-43^WT or ALS-associated mutant hTDP-43^Q331K, RACK1 RNAi knockdown alleviated retinal degeneration and improved locomotion. No degeneration was observed in flies upon RACK1 knockdown alone. <h3>Conclusions:</h3> Our data suggest that RACK1 knockdown is well-tolerated in cultured cells and fly neurons in vivo. It alleviates TDP-43 aggregation as well as associated global translational suppression in cultured cells. The significant amelioration of neurodegeneration by RACK1 knockdown in flies supports its therapeutic potential for treating TDP-43 proteinopathy in sporadic ALS and FTLD-TDP. <b>Disclosure:</b> Dr. Cashman has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Cashman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi-Tanabe. Dr. Cashman has stock in ProMIS Neurosciences. The institution of Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Cashman has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has a non-compensated relationship as a BoD memeber with ALS Society of BC that is relevant to AAN interests or activities. Beibei Zhao has received intellectual property interests from a discovery or technology relating to health care. Dr. Cowan has nothing to disclose. Miss Saraph has nothing to disclose. Mr. Christy has nothing to disclose. Ms. Coutts has nothing to disclose. Dr. Kaplan has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Kaplan has stock in ProMIS Neurosciences. Dr. Kaplan has received intellectual property interests from a discovery or technology relating to health care.

Effect of APOE ɛ4 genotype on age at onset and comorbid pathologies in multiple system atrophy (P8-11.004)

<h3>Objective:</h3> To elucidate the effect of apolipoprotein (APOE) ɛ4 genotype on age at onset and comorbid pathologies in multiple system atrophy (MSA). <h3>Background:</h3> APOE ɛ4 increases risk of Alzheimer’s disease (AD) and lowers age of onset of late-onset AD. In synucleinopathy, APOE ɛ4 has been reported to correlate with the severity of Lewy body pathology in Lewy body disease and to lower the age of onset of Parkinson’s disease. The association of APOE E4 with MSA is not well understood. <h3>Design/Methods:</h3> This study included 145 pathologically confirmed MSA patients (female 43%) in the Mayo Clinic Brain Bank. We reviewed the medical records to identify the age at onset at which motor or autonomic symptoms presented. MSA patients were divided into two groups: APOE ɛ4 carriers and non-carriers. We examined comorbid pathologies, including AD pathology, Lewy-related pathology, TDP-43 proteinopathy, argyrophilic grains, cerebral amyloid angiopathy (CAA), and aging-related tau astrogliopathy (ARTAG). We defined the presence of AD pathology based on the Braak neurofibrillary tangle stage and the Thal amyloid phase if both were equal or greater than 3. We compared the frequency of each pathology between APOE ɛ4 carriers and non-carriers. <h3>Results:</h3> Among 145 MSA patients, 26% (37/145) had APOE ɛ4 (female 41%) and 74% (108/145) had non-ɛ4 (female 44%). Age at onset was significantly younger in MSA with APOE ɛ4 than non-ɛ4 (P = 0.028, 56 ± 6 vs. 60 ± 10 years old). The frequency of CAA was significantly greater in MSA with APOE ɛ4 than non-ɛ4 (P = 0.0032, 43% vs. 18%); however, there was no significant difference in the frequency of AD pathology, Lewy-related pathology, TDP-43 proteinopathy, argyrophilic grains, and ARTAG. <h3>Conclusions:</h3> Our results indicate that APOE ɛ4 is associated with CAA in MSA, as well as lower age at onset, but not AD or Lewy-related pathologies. <b>Disclosure:</b> Dr. Sekiya has nothing to disclose. Dr. Koga has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Dickson has nothing to disclose.

Characterizing a Language Phenotype of Dementia with Lewy Bodies: A Clinicopathological Series (P13-6.009)

<h3>Objective:</h3> We report on three individuals with semantic variant primary progressive aphasia (svPPA) whose post-mortem pathology was consistent with diffuse neocortical Lewy body disease (LBD). We believe this is a heretofore unrecognized phenotype of LBD. <h3>Background:</h3> The present conception of primary dementias pairs clinical syndromes with neuropathologies, proven on necropsy or indirectly implicated by biomarkers. Each pairing is a clinicopathological entity. There is an increasing focus in the field of neurodegenerative disease to better characterize clinicopathological disorders, so as to target research and treatment approaches. SvPPA clinically manifests with progressive loss of semantic knowledge and is commonly associated with TDP-43 type C proteinopathy as well as Alzheimer’s(AD) and other tau pathologies. We report on three instances of svPPA associated with LBD pathology. We believe this is the first such report in the literature. <h3>Design/Methods:</h3> Our institution’s brain bank was queried for clinicopathological cases with a clinical diagnosis of svPPA and neuropathologic diagnosis of LBD. Three cases met the international consensus criteria for svPPA and were included in this study. <h3>Results:</h3> Three males aged 60–76 satisfied our inclusion criteria. Two subjects had significant temporal atrophy, and one had substantia nigral pallor. DAT scan was available in one subject, which was a negative study. All subjects fit the neuropathological consensus criteria for LBD with a diffuse neocortical distribution. In addition, all subjects had moderate vascular pathology and AD pathology (2-high ADNC, 1-intermediate). One case was also found with limbic associated Stage 1 TDP-43 proteinopathy. <h3>Conclusions:</h3> Here we propose a novel language variant of Lewy body disease. Although rare, LBD should be included as a differential diagnosis in individuals with svPPA. In the future, characterizing phenotypes of LBD will assist in more precise targeting of research and treatment strategies. <b>Disclosure:</b> Dr. Merhi has nothing to disclose. Anna C Sullivan has nothing to disclose. Miss Bhavaraju has nothing to disclose. Dr. Walker has nothing to disclose. Dr. Bieniek has nothing to disclose. Dr. Abdullah has nothing to disclose. Dr. Salardini has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. The institution of Dr. Salardini has received research support from NIH/NIA. The institution of Dr. Salardini has received research support from Taylor Family. Dr. Salardini has received publishing royalties from a publication relating to health care. Dr. Rini has nothing to disclose. An immediate family member of Dr. Parker has received personal compensation for serving as an employee of Rochal Industries, Rochal Parners. An immediate family member of Dr. Parker has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Sanara Med Tech. An immediate family member of Dr. Parker has stock in Sanara Med Tech. An immediate family member of Dr. Parker has stock in Rochal Industries. An immediate family member of Dr. Parker has stock in Rochal Parnters. The institution of Dr. Parker has received research support from Texas Alzheimer’s Research and Care Consortium. The institution of an immediate family member of Dr. Parker has received research support from Rochal Industries. An immediate family member of Dr. Parker has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Parker has received publishing royalties from a publication relating to health care. Dr. Parker has received personal compensation in the range of $500-$4,999 for serving as a Grand Rounds Speaker with Univ of Texas Tyler. An immediate family member of Dr. Parker has received personal compensation in the range of $0-$499 for serving as a NIH Review Committees Member with NIH. An immediate family member of Dr. Parker has a non-compensated relationship as a Chairwoman of the Board - Ann Salamone with BioMed SA that is relevant to AAN interests or activities.

Perry syndrome – the genetic, clinical, and pathological characteristics of the disease (P8-11.001)

<h3>Objective:</h3> To present an update on the genetic, clinical, and pathological characteristics of Perry syndrome (PS). <h3>Background:</h3> PS is a rare inherited neurodegenerative disorder characterized by parkinsonism, apathy/depression, weight loss, and hypoventilation, with distinct molecular (<i>DCTN1</i> mutations located on exon 2 within CAP-Gly domain) and neuropathological (TDP-43 pathology) characteristics. <h3>Design/Methods:</h3> We studied 27 members of the large new kindred from Louisiana and a new isolated case from Virginia. We performed two postmortem examinations. <h3>Results:</h3> We identified 7 cases suspected of PS in the Lousiana family. The mean age of first symptoms was 54 years, with non-motor symptoms (weight loss, neuropsychiatric symptoms) being the most common initial manifestation. Parkinsonism was present in 7/7, neuropsychiatric features in 4/7, weight loss in 5/7, respiratory symptoms in 3/7, dysautonomia in 4/7, and sleep disorders in 7/7 patients. Smell testing was unremarkable. Proband and another case tested positive for a novel <i>DCTN1</i> p.Gly67Val mutation within the CAP-Gly domain; the results of other cases were underway. The autopsy of the proband confirmed TDP-43 proteinopathy with predominant pallido-nigro-luysial involvement. The patient from Virginia developed apathy at 58 years, followed by depression, parkinsonism with upgaze limitation and pyramidal signs, weight loss, and pauses in breathing. She died at 69, and the pathological evaluation at autopsy revealed TDP-43 pathology with pallidonigral involvement, consistent with PS with known mutations in the <i>DCTN1</i> gene. Her genetic testing found a novel <i>DCTN1</i> Gly42Ser mutation, located on exon 2 but beyond the CAP-Gly domain. As her parents were not affected, we presume it was a <i>de novo</i> mutation. <h3>Conclusions:</h3> The heterogeneity of clinical and genetic characteristics of PS is increasingly recognized. Better understanding of the disease could translate into enhanced management strategy, improved quality of life, and extended life expectancy. <b>Disclosure:</b> Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for VM Media Ltd.. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Radoslaw Lipinski 90 Consulting. Dr. Dulski has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Ipsen. Dr. Dulski has received research support from Polish Neurological Society. Dr. Dulski has received research support from Polish National Agency for Academic Exchange. Dr. Koga has nothing to disclose. Dr. Tipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AbbVie. Dr. Tipton has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Alzheimer’s Tennessee. Dr. Tipton has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Charlotte County Medical Society, Inc. Mr. Ali has nothing to disclose. Audrey Strongosky has nothing to disclose. Miss Rose has nothing to disclose. Ms. Parrales has nothing to disclose. Ms. Dunmore has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology

Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.

Endogenous retroviruses can propagate TDP-43 proteinopathy

How does neurodegeneration spread in the brain? Leveraging TDP-43 fly models of amyotrophic lateral sclerosis (ALS), Chang and Dubnau recently reported that the endogenous retrovirus (ERV) mdg4 can trigger and transmit TDP-43 proteinopathy in vivo. Their results suggest that human ERVs could be targeted to develop future ALS therapies.