Pathogenesis Of Frontotemporal Lobar Degeneration Research Articles

HnRNP Pathologies in Frontotemporal Lobar Degeneration

Frontotemporal dementia (FTD) is the second most common form of young-onset (<65 years) dementia. Clinically, it primarily manifests as a disorder of behavioural, executive, and/or language functions. Pathologically, frontotemporal lobar degeneration (FTLD) is the predominant cause of FTD. FTLD is a proteinopathy, and the main pathological proteins identified so far are tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). As TDP-43 and FUS are members of the heterogeneous ribonucleic acid protein (hnRNP) family, many studies in recent years have expanded the research on the relationship between other hnRNPs and FTLD pathology. Indeed, these studies provide evidence for an association between hnRNP abnormalities and FTLD. In particular, several studies have shown that multiple hnRNPs may exhibit nuclear depletion and cytoplasmic mislocalisation within neurons in FTLD cases. However, due to the diversity and complex association of hnRNPs, most studies are still at the stage of histological discovery of different hnRNP abnormalities in FTLD. We herein review the latest studies relating hnRNPs to FTLD. Together, these studies outline an important role of multiple hnRNPs in the pathogenesis of FTLD and suggest that future research into FTLD should include the whole spectrum of this protein family.

Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage

Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.

Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.

Incidence and morphology of secondary TDP-43 proteinopathies: Part 1.

Transactive response DNA binding protein of 43 kDa (TDP-43) is considered to play an essential role in the pathogenesis of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Growing body of evidence indicate that pathological TDP-43 inclusions frequently occur in the context of other distinctive hallmark pathologies, referred to as secondary TDP-43 proteinopathies. Comorbid TDP-43 pathology is well-documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, or progressive supranuclear palsy. It may also appear as a consequence of less obvious disease etiologies, i.e. post-traumatic (chronic traumatic encephalopathy), neoplastic (pilocytic astrocytoma), or post-infectious (post-encephalitic parkinsonism). The aim of the present review was to evaluate the incidence, morphology, and role of TDP-43 pathology in the secondary TDP-43 proteinopathies. This article (Part 1) discussed TDP-43 pathology in more common neurodegenerative diseases, including Alzheimer's disease, Lewy body disease, Huntington's disease, multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy. A follow-up article (Part 2) will describe abnormal TDP-43 changes in rare neurodegenerative diseases or neurological diseases with nondegenerative etiology.

Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation.

The microtubule‐associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four‐repeat (4R)‐tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R‐tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R‐tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R‐tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R‐tau transcript and protein ratios. These elevated levels of 4R‐tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell‐type‐specific regulation and may inform and help on treatment of pre‐clinical tauopathies.

The role of the RNA binding protein HnRNP K in the pathogenesis of frontotemporal lobar degeneration.

HnRNP K is an RNA-binding protein belonging to the family of heterogeneous nuclear ribonucleoproteins (hnRNPs). Like other hnRNPs such as the better known TDP-43, hnRNP K is predominantly nuclear where it plays an important role in pre-mRNA splicing. HnRNPs can also shuttle to the cytoplasm and we find that hnRNP K is predominantly cytoplasmic in pyramidal neurons in Frontotemporal Lobar Degeneration (FTLD). The loss of nuclear hnRNPs in disease states is directly linked to splicing misregulation and aberrant RNA processing. Indeed, loss of nuclear TDP-43 leads to cryptic exon inclusion in gene targets and the generation of truncated proteins. We aimed to investigate changes in RNA processing and presence of cryptic events upon hnRNP K mislocalisation in FTLD. Bioinformatic analysis of a neuronal cell line with hnRNP K knockdown identified a set of cryptic events. We have validated these events using PCR amplification and gel electrophoresis in both SH-SY5Y cells with hnRNP K knockdown and in post-mortem human brain tissue. The loss of nuclear hnRNP K results in the inclusion of cryptic exons in multiple gene targets in both SH-SHY5Y cells with hnRNP K knockdown and FTLD brain regions exhibiting hnRNP K nuclear loss. The mislocalisation of hnRNP K from the nucleus to the cytoplasm in FTLD is associated with the inclusion of cryptic exons in multiple gene targets. This suggests that similarly to TDP-43, hnRNP K plays a crucial role in RNA processing and splicing regulation which when impaired could lead to transcriptional dysregulation and disease pathogenesis.

ALS-associated TBK1 variant p.G175S is defective in phosphorylation of p62 and impacts TBK1-mediated signalling and TDP-43 autophagic degradation

Mutations affecting SQSTM1 coding for p62 and TANK-Binding Kinase 1 (TBK1) have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TBK1 is a serine-threonine kinase that regulates p62's activity as an autophagy receptor via phosphorylation and also has roles in neuroinflammatory signalling pathways. The mechanisms underlying ALS and FTLD pathogenesis as a result of TBK1 mutations are incompletely understood, however, loss of TBK1 function can lead to dysregulated autophagy and mitophagy. Here, we report that an ALS-associated TBK1 variant affecting the kinase domain, p.G175S, is defective in phosphorylation of p62 at Ser-403, a modification critical for regulating its ubiquitin-binding function, as well as downstream phosphorylation at Ser-349. Consistent with these findings, expression of p.G175S TBK1 was associated with decreased induction of autophagy compared to wild type and reduced degradation of the ALS-linked protein TDP-43. Expression of wild type TBK1 increased NF-κB signalling ~300 fold in comparison to empty vector cells, whereas p.G175S TBK1 was unable to promote NF-κB signalling above levels observed in empty vector transfected cells. We also noted a hitherto unknown role for TBK1 as a suppressor of oxidative stress (Nrf2) signalling and show that p.G175S TBK1 expressing cells lose this inhibitory function. Our data suggest that TBK1 ALS mutations may broadly impair p62-mediated cell signalling, which ultimately may reduce neuronal survival, in addition TDP-43 was not efficiently degraded, together these effects may contribute to TBK1 mutation associated ALS and FTLD pathogenesis.

Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice.

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD‐related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.

The Clinical, Pathological, and Genetic Correlation in Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) presents diverse clinical symptoms, including psychiatric, behavioral, and language symptoms. Pathologically, it is a collective term of heterogeneous neurodegenerative disorders characterized by deposits of aberrant proteins, including tau, TAR DNA-binding protein of 43kDa (TDP-43), and fused in sarcoma (FUS), predominately in frontotemporal lobes. Recent genetic research has identified several causal and susceptibility genes of FTLD. Moreover, there is an emerging correlation between the clinical-pathological phenotypes and genetic factors. Such knowledge would contribute to further clarification of the pathogenesis of FTLD and the development of novel therapeutic interventions.

RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration.

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Pathogenesis of Frontotemporal Lobar Degeneration: Insights From Loss of Function Theory and Early Involvement of the Caudate Nucleus.

Frontotemporal lobar degeneration (FTLD) is a group of clinically, pathologically and genetically heterogeneous neurodegenerative disorders that involve the frontal and temporal lobes. Behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA) are three major clinical syndromes. TDP-43, FUS, and tau are three major pathogenetic proteins. In this review, we first discuss the loss-of-function mechanism of FTLD. We focus on FUS-associated pathogenesis in which FUS is linked to tau by regulating its alternative splicing machinery. Moreover, FUS is associated with abnormalities in post-synaptic formation, which can be an early disease marker of FTLD. Second, we discuss clinical and pathological aspects of FTLD. Recently, FTLD and amyotrophic lateral sclerosis (ALS) have been recognized as the same disease entity; indeed, nearly all sporadic ALS cases show TDP-43 pathology irrespective of FTD phenotype. Thus, investigating early structural and network changes in the FTLD/ALS continuum can be useful for developing early diagnostic markers of FTLD. MRI studies have revealed the involvement of the caudate nucleus and its anatomical networks in association with the early phase of behavioral/cognitive decline in FTLD/ALS. In particular, even ALS patients with normal cognition have shown a significant decrease in structural connectivity between the caudate head networks. In pathological studies, FTLD/ALS has shown striatal involvement of both efferent system components and glutamatergic inputs from the cerebral cortices even in ALS patients. Thus, the caudate nucleus may be primarily associated with behavioral abnormality and cognitive involvement in FTLD/ALS. Although several clinical trials have been conducted, there is still no therapy that can change the disease course in patients with FTLD. Therefore, there is an urgent need to establish a strategy for predominant sporadic FTLD cases.

The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

IntroductionCell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP‐43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD).MethodsWe investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal‐associated membrane proteins 1 (LAMP‐1) and 2 (LAMP‐2), cathepsin D (CTSD) and microtubule‐associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi‐quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx).ResultsLower levels of neuronal LAMP‐1 immunostaining were present in the DG and Tcx in FTLD‐tau compared to FTLD‐TDP. There was less LAMP‐1 immunostaining in FTLD‐tau with MAPT mutations, and FTLD‐tau with Pick bodies, compared to FTLD‐TDP types A and B, and less LAMP‐1 immunostaining in FTLD‐TDP type C than in FTLD‐TDP types A and B. There was greater LAMP‐1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP‐2, CTSD, EEA‐1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD‐TDP and FTLD‐tau.ConclusionsThe underlying pathological mechanism in FTLD‐tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP‐43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

The Role of TDP‐43 in the Pathogenesis of Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is one of the most common neurodegernation diseases, especially in the dementia. TDP‐43 is a multifunctional DNA/RNA‐binding factor, which has been identified as the major disease protein of frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) and amyotrophic lateral sclerosis (ALS). TDP‐43 has been known mainly as a nuclear protein, with two RNA‐recognition motifs (RRM), RRM1 and RRM2, and a glycine‐rich region in its C‐terminus. However, the role of TDP‐43 in the pathogenesis of FTLD‐U has remained unknown. Therefore, to know how TDP‐43 pathology results in neuronal death in FTLD‐U may provide a therapeutic strategy to FTLD‐U. In this study, to test whether aberrant cell cycle activity and DNA damage involve in the neuronal death results from TDP pathology, the expression level of cell cycle associated genes and DNA damage marker had been examined. Form the result, cell cycle re‐expression and DNA damage occur in the TDP‐43 Tg mice and human brain tissues.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43-immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.

Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns.

The 'prion-like' transfer of pathogenic proteins may play a role in the pathogenesis of frontotemporal lobar degeneration (FTLD). Propagation of such proteins along anatomical pathways may give rise to specific spatial patterns of the 'signature' neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of the NCI were compared in three molecular subtypes of FTLD: (1) two variants of FTLD-tau, viz. cortico-basal degeneration (CBD) and Pick's disease (PiD), (2) FTLD with transactive response (TAR) DNA-binding protein 43(TDP-43)-immunoreactive inclusions (FTLD-TDP), and (3) FTLD with 'fused in sarcoma' (FUS)-immunoreactive inclusions (FTLD-FUS). Regardless of molecular pathology, the NCI in the frontal and temporal cortex were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating the dimension of cell columns associated with the cortico-cortical pathways. Clusters of NCI were significantly larger in FTLD-tau compared with FTLD-TDP and FTLD-FUS. The data suggest that cortical NCI in different molecular subtypes of FTLD all share a similar spatial pattern in the frontal and temporal cortex consistent with a 'prion-like' spread of pathological proteins along anatomical pathways. However, a more selective group of neurons appears to be affected in FTLD-TDP and FTLD-FUS than in FTLD-tau.

Frontotemporal Lobar Degeneration and MicroRNAs.

Frontotemporal lobar degeneration (FTLD) includes a spectrum of disorders characterized by changes of personality and social behavior and, often, a gradual and progressive language dysfunction. In the last years, several efforts have been fulfilled in identifying both genetic mutations and pathological proteins associated with FTLD. The molecular bases undergoing the onset and progression of the disease remain still unknown. Recent literature prompts an involvement of RNA metabolism in FTLD, particularly microRNAs (miRNAs). Dysregulation of miRNAs in several disorders, including neurodegenerative diseases, and increasing importance of circulating miRNAs in different pathologies has suggested to implement the study of their possible application as biological markers and new therapeutic targets; moreover, miRNA-based therapy is becoming a powerful tool to deepen the function of a gene, the mechanism of a disease, and validate therapeutic targets. Regarding FTLD, different studies showed that miRNAs are playing an important role. For example, several reports have evaluated miRNA regulation of the progranulin gene suggesting that it is under their control, as described for miR-29b, miR-107, and miR-659. More recently, it has been demonstrated that TMEM106B gene, which protein is elevated in FTLD-TDP brains, is repressed by miR-132/212 cluster; this post-transcriptional mechanism increases intracellular levels of progranulin, affecting its pathways. These findings if confirmed could suggest that these microRNAs have a role as potential targets for some related-FTLD genes. In this review, we focus on the emerging roles of the miRNAs in the pathogenesis of FTLD.

Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice.

Granulin (GRN) mutations have been identified in familial frontotemporal lobar degeneration patients with ubiquitin pathology. GRN transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in frontotemporal lobar degeneration pathogenesis. Moreover, recent findings indicate that GRN mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer disease and corticobasal degeneration. To investigate the potential influence of a decline in PGRN protein on tau accumulation, P301L tau transgenic mice were interbred with GRN-deficient mice, producing P301L tau transgenic mice harboring the GRN hemizygote. Brains were collected from 13- and 19-month-old mice, and sequential extraction of proteins, immunoblotting, and immunohistochemical analyses were performed. Immunoblotting analysis revealed that tau phosphorylation was accelerated in the Tris-saline soluble fraction of 13-month-old and in the sarkosyl-insoluble fraction of 19-month-old P301L tau/GRN hemizygotes compared with those in fractions from P301L tau transgenic mice. Activity of cyclin-dependent kinases was also upregulated in the brains of P301L tau/GRN hemizygote mice. Although the mechanisms involved in these findings remain unknown, our data suggest that a reduction in PGRN protein might contribute to phosphorylation and intraneuronal accumulation of tau.

Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa–Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge. To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). Neuronal TDP-43 pathological changes and neuronal loss. Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.

The role of TDP-43 in the pathogenesis of ALS and FTLD

TDP-43 (TAR DNA-binding protein 43) is an hnRNP (heterogeneous nuclear ribonucleoprotein) protein whose role in cellular processes has come to the forefront of neurodegeneration research after the observation that it is the main component of brain inclusions in ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration) patients. Functionally, this aberrant aggregation and mislocalization implies that, in the affected neurons, transcripts regulated by TDP-43 may be altered. Since then, a considerable amount of data has been gathered on TDP-43 interactions and on the genes that are influenced by its absence or overexpression. At present, however, most of these data come from high-throughput searches, making it problematic to separate the direct effects of TDP-43 from secondary misregulations occurring at different levels of the gene expression process. Furthermore, our knowledge of the biochemistry of TDP-43, its RNA-binding characteristics, its nuclear and cytoplasmic targets, and the details of its interactions with other proteins is still incomplete. The understanding of these features could hold the key for uncovering TDP-43's role in ALS and FTLD pathogenesis. We describe in the present paper our work on TDP-43 RNA binding, self-regulation and aggregation processes, and attempt to relate them to the neurodegenerative pathologies.