This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised –– including deficits in social cognition and language – but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neu...

/pdf/amyotrophic-lateral-sclerosis-frontotemporal-spectrum-3xmp1q6vcb.pdf

Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria

TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits as inclusion bodies in the brain and spinal cord of the patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While majority of the ALS cases (90-95%) are sporadic (sALS), among the familial ALS cases 5-10% involve the inheritance of mutations in the TARDBP gene and the remaining (90-95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS, and NEK1 etc. Strikingly however, majority of the sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unravelling the molecular mechanisms of the TDP-43 pathology, seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43’s pathology in ALS. We discuss the roles of TDP-43’s mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43’s amyloid-like in vitro aggregation, its physiological versus pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies towards TDP-43 disaggregation and ALS therapeutics.

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.

https://www.cell.com/neuron/pdf/S0896-6273(20)30653-X.pdf

ALS Genetics: Gains, Losses, and Implications for Future Therapies.

Autophagy Receptors and Neurodegenerative Diseases.

Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseasesAbbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2021.1926656

Autophagy and ALS: mechanistic insights and therapeutic implications.

Objective
The existing screening batteries assessing multiple neuropsychological functions are not specific to amyotrophic lateral sclerosis (ALS) patients and are limited to their physical dysfunctions, whereas category cognitive tests are too time-consuming to assess all the domains. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was recently developed as a fast and easy cognitive screening tool specifically designed for patients. The purpose of the study was to validate the effectiveness of the Chinese version in Chinese ALS populations.

/pdf/the-edinburgh-cognitive-and-behavioural-als-screen-in-a-4wm7kzn1v3.pdf

The Edinburgh Cognitive and Behavioural ALS Screen in a Chinese Amyotrophic Lateral Sclerosis Population

The purpose of this study was to assess the frequency of optineurin (OPTN) mutation in amyotrophic lateral sclerosis (ALS) patients from mainland China, as well as to characterize the relationship between OPTN mutation and clinical phenotypes. We examined the coding region of OPTN in 511 unrelated Chinese sporadic ALS (SALS) subjects and 204 healthy controls using a PCR direct sequencing strategy. Nine OPTN variants were identified, of which four were novel missense mutations: c.407C > T (p.A136V), c.1184A > G (p.K395R), c.1352T > C (p.I451T), and c.1546G > C (p.E516Q) (all heterozygous). The remaining five variants were already present in single nucleotide polymorphism databases. Patients with OPTN mutations were characterized by spinal onset, although they showed differences in disease progression. In conclusion, this study provides a genetic epidemiological characterization of OPTN mutations in Chinese patients, and our results are consistent with the proposition that such mutations are common in Asian populations.

Optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in China.

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The Edinburgh Cognitive and Behavioural ALS Screen in a Chinese Amyotrophic Lateral Sclerosis Population

Optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in China.