Alterations in Tau Metabolism in ALS and ALS-FTSD

There is increasing acceptance that amyotrophic lateral sclerosis (ALS), classically considered a neurodegenerative disease affecting almost exclusively motor neurons, is syndromic with both clinical and biological heterogeneity. This is most evident in its association with a broad range of neuropsychological, behavioral, speech and language deficits [collectively termed ALS frontotemporal spectrum disorder (ALS-FTSD)]. Although the most consistent pathology of ALS and ALS-FTSD is a disturbance in TAR DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein (tau) metabolism can also be observed in ALS-FTSD, most prominently as pathological phosphorylation at Thr175 (pThr175tau). pThr175 has been shown to promote exposure of the phosphatase activating domain (PAD) in the tau N-terminus with the consequent activation of GSK3β mediated phosphorylation at Thr231 (pThr231tau) leading to pathological oligomer formation. This pathological cascade of tau phosphorylation has been observed in chronic traumatic encephalopathy with ALS (CTE-ALS) and in both in vivo and in vitro experimental paradigms, suggesting that it is of critical relevance to the pathobiology of ALS-FTSD. It is also evident that the co-existence of alterations in the metabolism of TDP-43 and tau acts synergistically in a rodent model to exacerbate the pathology of either.

Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis

Natural Product Communications ◽

10.1177/1934578x211030815 ◽

2021 ◽

Vol 16 (10) ◽

pp. 1934578X2110308

Author(s):

Fahad Hassan Shah ◽

Song Ja Kim

Keyword(s):

Motor Neurons ◽

Major Gene ◽

Dna Binding Protein ◽

Chemical Affinity ◽

Drug Candidates ◽

Medicinal Compounds ◽

Candidate Drug ◽

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.

Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

Journal of Clinical Medicine ◽

10.3390/jcm9010261 ◽

2020 ◽

Vol 9 (1) ◽

pp. 261 ◽

Cited By ~ 2

Author(s):

Tereza Filipi ◽

Zuzana Hermanova ◽

Jana Tureckova ◽

Ondrej Vanatko ◽

Miroslava Anderova

Keyword(s):

Motor Neurons ◽

Current Knowledge ◽

Gene Mutations ◽

Cell Types ◽

In Vivo Models ◽

Cell Therapies ◽

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

Human Molecular Genetics ◽

10.1093/hmg/ddz190 ◽

2019 ◽

Vol 28 (21) ◽

pp. 3584-3599 ◽

Cited By ~ 4

Author(s):

Matthew G Williamson ◽

Mattéa J Finelli ◽

James N Sleigh ◽

Amy Reddington ◽

David Gordon ◽

...

Keyword(s):

Motor Neurons ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Gene Encoding ◽

Over Expression ◽

Neuromuscular Abnormalities ◽

And Function ◽

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2012/323261 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Yoshiaki Furukawa

Keyword(s):

Superoxide Dismutase ◽

Motor Neurons ◽

Wild Type ◽

Sporadic Als ◽

Familial Form ◽

Recent Developments ◽

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

Science Advances ◽

10.1126/sciadv.abf8660 ◽

2021 ◽

Vol 7 (30) ◽

pp. eabf8660

Author(s):

Nicol Birsa ◽

Agnieszka M. Ule ◽

Maria Giovanna Garone ◽

Brian Tsang ◽

Francesca Mattedi ◽

...

Keyword(s):

Phase Separation ◽

Motor Neurons ◽

Rna Binding ◽

Fragile X ◽

Protein Translation ◽

Fused In Sarcoma ◽

Mental Retardation Protein ◽

FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation.

Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

Cells ◽

10.3390/cells9112413 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2413

Author(s):

Azin Amin ◽

Nirma D. Perera ◽

Philip M. Beart ◽

Bradley J. Turner ◽

Fazel Shabanpoor

Keyword(s):

Motor Neurons ◽

Protein Aggregates ◽

Misfolded Proteins ◽

Protein Aggregate ◽

In Vivo Models ◽

Primary Stress ◽

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa072 ◽

2021 ◽

Author(s):

Pengcheng Ma ◽

Yuwei Li ◽

Huishan Wang ◽

Bingyu Mao

Keyword(s):

Motor Neurons ◽

Regulatory Protein ◽

E3 Ligase ◽

Subcellular Location ◽

Spinal Motor Neurons ◽

Ubiquitin E3 Ligase ◽

Abstract TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis (ALS) cases, suggesting a central pathogenic role of this regulatory protein. Clarifying the molecular mechanism controlling TDP43 stability and subcellular location might provide important insights into ALS therapy. The ubiquitin E3 ligase RNF220 is involved in different neural developmental processes through various molecular targets in the mouse. Here, we report that the RNF220+/- mice showed progressively decreasing mobility to different extents, some of which developed typical ALS pathological characteristics in spinal motor neurons, including TDP43 cytoplasmic accumulation, atrocytosis, muscle denervation, and atrophy. Mechanistically, RNF220 interacts with TDP43 in vitro and in vivo and promotes its polyubiquitination and proteasomal degradation. In conclusion, we propose that RNF220 might be a modifier of TDP43 function in vivo and contribute to TDP43 pathology in neurodegenerative disease like ALS.

Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01112-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Xuebing Ding ◽

Zhi Xiang ◽

Chi Qin ◽

Yongkang Chen ◽

Haiyan Tian ◽

...

Keyword(s):

Primary Motor Cortex ◽

Direct Evidence ◽

Pyramidal Tract ◽

Dna Binding Protein ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Potential Mechanism ◽

AbstractTransactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy.

A cell-penetrant peptide blocking C9ORF72-repeat RNA nuclear export suppresses neurodegeneration

10.1101/2021.05.23.445325 ◽

2021 ◽

Author(s):

Lydia M Castelli ◽

Alvaro Sanchez-Martinez ◽

Ya-Hui Lin ◽

Santosh Kumar Upadhyay ◽

Adrian Higginbottom ◽

...

Keyword(s):

Motor Neurons ◽

Nuclear Export ◽

Promising Alternative ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

A Cell ◽

Models Of Disease ◽

Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum of incurable debilitating neurodegenerative diseases. Here, we report a novel ALS/FTD drug concept with in vivo and in vitro therapeutic activity in preclinical models of C9ORF72-ALS/FTD. Our data demonstrate that supplementation or oral administration of a cell-penetrant peptide, which competes with the SRSF1:NXF1 interaction, confers neuroprotection by inhibiting the nuclear export of pathological C9ORF72-repeat transcripts in various models of disease including primary neurons, patient-derived motor neurons and Drosophila. Our drug-like rationale for disrupting the nuclear export of microsatellite repeat transcripts in neurological disorders provides a promising alternative to conventional small molecule inhibitors often limited by poor blood-brain barrier penetrance.

Exposure of a cryptic Hsp70 binding site determines the cytotoxicity of the ALS-associated SOD1-mutant A4V

Protein Engineering Design and Selection ◽

10.1093/protein/gzaa008 ◽

2019 ◽

Vol 32 (10) ◽

pp. 443-457 ◽

Cited By ~ 2

Author(s):

Filip Claes ◽

Stanislav Rudyak ◽

Angela S Laird ◽

Nikolaos Louros ◽

Jacinte Beerten ◽

...

Keyword(s):

Binding Site ◽

Motor Neurons ◽

Zebrafish Model ◽

Surveillance Network ◽

Denatured State ◽

Inclusion Body Formation ◽

Sod1 Mutant ◽

Abstract The accumulation of toxic protein aggregates is thought to play a key role in a range of degenerative pathologies, but it remains unclear why aggregation of polypeptides into non-native assemblies is toxic and why cellular clearance pathways offer ineffective protection. We here study the A4V mutant of SOD1, which forms toxic aggregates in motor neurons of patients with familial amyotrophic lateral sclerosis (ALS). A comparison of the location of aggregation prone regions (APRs) and Hsp70 binding sites in the denatured state of SOD1 reveals that ALS-associated mutations promote exposure of the APRs more than the strongest Hsc/Hsp70 binding site that we could detect. Mutations designed to increase the exposure of this Hsp70 interaction site in the denatured state promote aggregation but also display an increased interaction with Hsp70 chaperones. Depending on the cell type, in vitro this resulted in cellular inclusion body formation or increased clearance, accompanied with a suppression of cytotoxicity. The latter was also observed in a zebrafish model in vivo. Our results suggest that the uncontrolled accumulation of toxic SOD1A4V aggregates results from insufficient detection by the cellular surveillance network.