Motor Neuron Dysfunction Research Articles

Linking epigenetic dysregulation, mitochondrial impairment, and metabolic dysfunction in SBMA motor neurons.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Using gene expression analysis and ChIP sequencing, we mapped transcriptional changes in genetically engineered patient stem cell-derived motor neurons. We found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. We detected reduced histone acetylation, along with decreased expression of genes encoding compensatory metabolic proteins and reduced substrate availability for mitochondrial function. Furthermore, we found that pyruvate supplementation corrected this deficiency and improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.

Electrodiagnosis of Amyotrophic Lateral Sclerosis: A Review of Existing Guidelines.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper motor neurons in the motor cortex and lower motor neurons (LMN) in the brainstem and spinal cord, resulting in a progressive functional impairment. Neurophysiology is a diagnostic tool to detect dysfunction of upper motor neurons and LMN, even when the changes are subclinical. Electromyography is the standard neurophysiological investigation to detect LMN changes, which is essential to exclude mimicking disorders and attain early diagnosis. Recently, Awaji criteria was proposed to support ALS diagnosis, in these criteria fasciculation potentials associated with neurogenic motor unit potentials represents a sufficient marker of LMN involvement, in each muscle. Many studies have confirmed that Awaji criteria are more sensitive, permitting earlier diagnosis without loss of specificity when compared with the revised El Escorial criteria. Fasciculations are easily detected by ultrasound; increasingly, this technique has been used to diagnose ALS, combined with electromyography. This combination can increase diagnostic accuracy. Many techniques for estimating the number of motor units have been proposed, they are useful to quantify LMN loss. Electrical impedance myography is an emerging technique with great potential to monitor ALS progression. Neurophysiological investigation of upper motor neuron dysfunction is difficult in ALS, detecting decreased cortical inhibition by threshold tracking cortical magnetic stimulation is a promising method, which needs to be validated in different centers.

Spreading in ALS: The relative impact of upper and lower motor neuron involvement.

ObjectiveTo investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement.MethodsWe assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, and thoracic regions Non‐linear regression analysis was applied to fit the data to a model that described the relation between two random variables, graphically represented by an inverse exponential curve. We analyzed the probability, rate of spread, and both combined (area under the curve).ResultsWe found that progression was more likely and quicker to or from the region of onset to close spinal regions. When the disease had a limb onset, bulbar motor neurons were more resistant. Furthermore, in the same time frame more patients progressed from bulbar to lower limbs than vice‐versa, whether predominantly UMN or LMN involvement. Patients with initial thoracic involvement had a higher probability for rapid change. The presence of predominant UMN signs was associated with a faster caudal progression.InterpretationContiguous progression was leading pattern, and predominant UMN involvement is important in shortening the time for cranial‐caudal spread. Our results can best be fitted to a model of independent LMN and UMN degeneration, with regional progression of LMN degeneration mostly by contiguity. UMN lesion causes an acceleration of rostral‐caudal LMN loss.

Corticomotor Excitability in Two Kinds of Motor Neuron Diseases: A Study on the Patients With Amyotrophic Lateral Sclerosis and Poliomyelitis Survivors.

To examine upper motor neuron functions comparatively in patients with amyotrophic lateral sclerosis (ALS) and poliomyelitis survivors using transcranial magnetic stimulation (TMS) methods. Single- and paired-pulse TMS with conventional methods and the triple-stimulation technique were performed by recording from the abductor digiti minimi and abductor pollicis brevis muscles in 31 patients with ALS, 18 patients with poliomyelitis survivors, and 21 controls. Nine patients were diagnosed as having postpoliomyelitis syndrome after a 6-month follow-up. Triple-stimulation technique and some of conventional TMS studies were able to distinguish ALS from both poliomyelitis survivors and controls. A reduced ipsilateral silent period in abductor pollicis brevis muscles was the only parameter to show a significant difference when comparing thenar and hypothenar muscles in ALS. No significant difference was present in any TMS parameters between the postpoliomyelitis syndrome and non-postpoliomyelitis syndrome groups. Conventional TMS and particularly triple-stimulation technique studies are helpful in disclosing upper motor neuron dysfunction in ALS. The results of this study might favor the cortical hypothesis for split hand in ALS, but they revealed no significant indication for upper motor neuron dysfunction in postpoliomyelitis syndrome.

Cerebrospinal fluid MFG-E8 as a promising biomarker of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease resulting in the dysfunction of upper and lower motor neurons. Biomarkers in fluid have been used to monitor the disease and its progression. Milk fat globule-EGF factor 8 (MFG-E8) is an inflammation modulator, which is involved in the pathogenesis of neurodegenerative diseases. We here took this study to evaluate the predictive value of MFG-E8 in ALS. This study consisted of 19 patients with ALS and 15 healthy controls. Cerebrospinal fluid (CSF) were collected from all participants and tested for the levels of MFG-E8, neurofilament light (NFL), and heavy chain (NFH). The correlations between MFG-E8 and NFL, NFH, ALS severity, cognitive status, and forced vital capacity (FVC) were analyzed. We found that MFG-E8 performs well in distinguishing ALS from controls, with relatively higher level of MFG-E8 in ALS subjects, than controls. Moreover, MFG-E8 negatively correlated with the revised ALS function rating scale (ALS-FRS), but not with the levels of NFL and NFH, disease duration, progression rate, mini-mental state examination (MMSE), and FVC. The study proved that CSF MFG-E8 helps distinguish ALS from controls. However, the protein in CSF negatively predicted disease severity.

ALS-associated genes in SCA2 mouse spinal cord transcriptomes.

The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.

Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: A case series

BackgroundHeat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs.We present five patients with mutations in HSPB1 who presented with a range of clinical phenotypes related to different patterns of motor neuron dysfunction. Three of these mutations have not been previously reported. MethodsPatients were seen at our neuromuscular or amyotrophic lateral sclerosis (ALS) clinics. Gene sequencing was carried out as part of diagnostic investigations. Detailed clinical and electrophysiologic data was collected. ResultsFive patients had variants of HSPB1. Three patients had a hereditary length-dependent sensori-motor axonal neuropathy consistent with Charcot Marie Tooth type 2 (CMT2); two of these patients carried novel mutations in the C-terminal region (p.Glu186* and p.Pro170Thr). One patient had the clinical picture of ALS and a novel missense mutation (p.Arg27Leu) in the N-terminal region. Another patient had the phenotype of hereditary spastic paraparesis (HSP) associated with a missense mutation (p.Gly84Arg) already described in families with CMT or dHMN. ConclusionThis study describes three novel mutations of HSPB1 and describes two patients with upper motor neurone signs associated with HSPB1 mutations.

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

Early Surgical Decompression Ameliorates Dysfunction of Spinal Motor Neuron in Patients With Acute Traumatic Central Cord Syndrome: An Ambispective Cohort Analysis.

An ambispective cohort analysis. The aim of this study was to investigate the impact of early (≤2 weeks) versus delayed (>2 weeks) surgical intervention on the spinal motor neurons at and distal to injury site in acute traumatic central cord syndrome (ATCCS). Accumulating evidence demonstrated degeneration in distal lower motor neurons (LMNs) following spinal cord injury, and this secondary degeneration may exacerbate motor impairments and limit spontaneous motor recovery. However, few studies involved this pathological process in ATCCS. Motor unit number estimation (MUNE) was performed on both abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) in 69 ATCCS patients (early vs. delayed surgical-treatment: 29 vs. 35) and 42 healthy subjects. All patients were assessed by American spinal injury association and Medical Research Council scales. These examinations and disabilities of arm, shoulder, and hand (c) questionnaire were administered approximately 21 months after operation in 65 of these patients. Preoperatively, MUNE values were lower in cervical-innervated muscles of ATCCS patients than in those of controls, and reduced motor units were observed in lumbosacral-innervated muscles in ATCCS patients with preoperative duration over 6 months (P < 0.05). Increased motor unit size without modification of MUNE values was found in delayed-surgical patients, whereas early-surgical patients mainly showed increased MUNE values in tested muscles between two assessments (P < 0.05). The postoperative follow-up analysis identified larger motor unit size and relatively fewer motor units in tested muscles, as well as higher DASH scores, in delayed-surgical patients than in early-surgical patients (P < 0.05). ATCCS has adverse downstream effects on the LMNs distal to injury site. Surgical intervention within 2 weeks after injury in ATCCS patients may be beneficial in ameliorating dysfunction of spinal motor neurons at and distal to injury site, reducing secondary motor neuron loss, and eventually improving neurologic outcomes. 3.

Occasional essay: Upper motor neuron syndrome in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify...

Acute Flaccid Myelitis: Current Status and Diagnostic Challenges.

Acute flaccid myelitis (AFM) is a sudden-onset polio-like neuromuscular disability found commonly in young children. There is an increasing incidence of confirmed AFM cases in the USA and other countries in recent years, and in association with nonpolio enterovirus infection. This represents a significant challenge to clinicians and causes significant concern to the general public. Acute flaccid paralysis (AFP) is the long-known limb paralytic syndrome caused by a viral pathogen. AFM is a subset of AFP that is also characterized by a limb paralytic condition, but it has certain distinct features such as lesions in magnetic resonance imaging of the spinal cord gray matter. AFM leads to spinal cord, brainstem, or motor neuron dysfunction. The clinical phenotypes, pathology, and patient presentation of AFM closely mimic AFP. This article provides a concise overview of our current understanding of AFM and the clinical features that distinguish AFM from AFP and similar other neurological infectious and autoimmune diseases or disorders. We also discuss the diagnosis, clinical pathology, possible pathogenetic mechanisms, and currently available therapies.

Diffusion tensor imaging evidence of corticospinal pathway involvement in frontotemporal lobar degeneration

Motor neuron dysfunctions (MNDys) in Frontotemporal Lobar Degeneration (FTLD) have been consistently reported. Clinical and neurophysiological findings proved a variable range of pathological changes, also affecting the corticospinal tract (CST).This study aims to assess white-matter microstructural alterations in a sample of patients with FTLD, and to evaluate the relationship with MNDys.Fifty-four FTLD patients (21 bvFTD, 16 PPA, 17 CBS) and 36 healthy controls participated in a Diffusion Tensor Imaging (DTI) study. We analyzed distinctive and common microstructural alteration patterns across FTLD subtypes, including those affecting the CST, and performed an association analysis between CST integrity and the presence of clinical and/or neurophysiological signs of MNDys.The majority of FTLD patients showed microstructural changes in the motor pathway with a high prevalence of CST alterations also in patients not displaying clinical and/or neurophysiological signs of MNDys.Our results suggest that subtle CST alterations characterize FTLD patients regardless to the subtype. This may be due to the spread of the pathological process to the motor system, even without a clear clinical manifestation of MNDys.

Evaluation for Late Nerve Transfer Surgery in Spinal Cord Injury: Predicting the Degree of Lower Motor Neuron Injury

Nerve transfer surgery is used to restore upper extremity function following cervical spinal cord injury (SCI) with substantial variation in outcomes. The injury pattern in SCI is complex and can include isolated upper motor neuron (UMN) and combined UMN/lower motor neuron (LMN) dysfunction. The purpose of the study was to determine the most effective diagnostic technique for determining suitable candidates for nerve transfer surgery in SCI. Medical records were reviewed of patients who had nerve transfers to restore upper extremity function in SCI. Data collected included (1) preoperative clinical examination and electrodiagnostic testing; (2) intraoperative neuromuscular stimulation (NMS); and (3) nerve histopathology. Preoperative, intraoperative, and postoperative data were compared to identify predictors of isolated UMN versus combined UMN/LMN injury patterns. The study sample included 22 patients with 50 nerve transfer surgeries and included patients ranging from less than 1 year to over a decade post-SCI. Normal recipient nerve conduction studies (NCS) before surgery corresponded to the intraoperative presence of recipient NMS and postoperative histopathology that showed normal nerve architecture. Conversely, abnormal recipient NCS before surgery corresponded with the absence of recipient NMS during surgery and patterns of denervation on postoperative histopathology. Normal donor preoperative manual muscle testing corresponded with the presence of donor NMS during surgery and normal nerve architecture on postoperative histopathology. An EMG of corresponding musculature did not correspond with intraoperative donor or recipient NMS or histopathological findings. NCS better predict patterns of injury in SCI than EMG. This is important information for clinicians evaluating people for late nerve transfer surgery even years post-SCI. Diagnostic II.

MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination

The combination of congenital bilateral perisylvian syndrome (CBPS) with lower motor neuron dysfunction remains unusual and suggests a potential common genetic insult affecting basic neurodevelopmental processes. Here we identify a putatively pathogenic missense mutation in the MCF2 gene in a boy with CBPS. Using in utero electroporation to genetically manipulate cortical neurons during corticogenesis, we demonstrate that the mouse Mcf2 gene controls the embryonic migration of cortical projection neurons. Strikingly, we find that the CBPS‐associated MCF2 mutation impairs cortical laminar positioning, supporting the hypothesis that alterations in the process of embryonic neuronal migration can lead to rare cases of CBPS.

Repeater F-waves in amyotrophic lateral sclerosis: Electrophysiologic indicators of upper or lower motor neuron involvement?

ObjectiveTo extract insight about the mechanism of repeater F-waves (Frep) by exploring their correlation with electrophysiologic markers of upper and lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). MethodsThe correlations of Frep parameters with clinical scores and the results of neurophysiological index (NI), MScanfit MUNE, F/M amplitude ratio (F/M%), single and paired-pulse transcranial magnetic stimulation (TMS), and triple stimulation technique (TST) studies, recorded from abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles of 35 patients with ALS were investigated. ResultsFrep parameters were correlated with NI and MScanfit MUNE in ADM muscle and F/M% in both muscles. None of the Frep parameters were correlated with clinical scores or TST and TMS measures. While the CMAP amplitudes were similar in the two recording muscles, there was a more pronounced decrease of F-wave persistence in APB, probably heralding the subsequent split hand phenomenon. ConclusionOur findings suggest that the presence and density of Freps are primarily related to the degree of lower motor neuron loss and show no correlation with any of the relatively extensive set of parameters for upper motor neuron dysfunction. SignificanceFreps are primarily related to lower motor neuron loss in ALS.

MicroRNA-Based Separation of Cortico-Fugal Projection Neuron-Like Cells Derived From Embryonic Stem Cells

The purification of pluripotent stem cell-derived cortico-fugal projection neurons (PSC-CFuPNs) is useful for disease modeling and cell therapies related to the dysfunction of cortical motor neurons, such as amyotrophic lateral sclerosis (ALS) or stroke. However, no CFuPN-specific surface markers for the purification are known. Recently, microRNAs (miRNAs) have been reported as alternatives to surface markers. Here, we investigated this possibility by applying the miRNA switch, an mRNA technology, to enrich PSC-CFuPNs. An array study of miRNAs in mouse fetal brain tissue revealed that CFuPNs highly express miRNA-124-3p at E14.5 and E16.5. In response, we designed a miRNA switched that responds to miRNA-124-3p and applied it to mouse embryonic stem cell (ESC)-derived cortical neurons. Flow cytometry and quantitative polymerase chain reaction (qPCR) analyses showed the miRNA-124-3p switch enriched CFuPN-like cells from this population. Immunocytechemical analysis confirmed vGlut1/Emx1/Bcl11b triple positive CFuPN-like cells were increased from 6.5 to 42%. Thus, our miRNA-124-3p switch can uniquely enrich live CFuPN-like cells from mouse ESC-derived cortical neurons.

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.

Impaired EWSR1 activity leads to oligodendrocyte dysfunction and demyelination of motor neurons in amyotrophic lateral sclerosis (ALS)

Impaired EWSR1 activity leads to oligodendrocyte dysfunction and demyelination of motor neurons in amyotrophic lateral sclerosis (ALS)

Hyperexcitability precedes motoneuron loss in the Smn2B/- mouse model of spinal muscular atrophy.

Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/- mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/- mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/- motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9-10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/- motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process.NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/- model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9-10, and specific electrophysiological changes in Smn2B/- motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.

Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43

ABSTRACTA shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of ATG7, a critical gene required for macroautophagy/autophagy. Mouse and Drosophila models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology.Abbreviations: ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43.