Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy

Casterton, Rebecca L.; Hunt, Rachel J.; Fanto, Manolis

doi:10.1016/j.jmb.2020.02.018

Cited by 24 publications

(24 citation statements)

References 209 publications

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“…The bleak facts in sporadic PD is that the clinical motor manifestations are late 170,171 with no possibility of reversing the extensive damage to dopaminergic cells, while in AD, the cognitive deficits develop very early and deeply compromise the potential academic, social and economic goals in young subjects.The TDP-43 pathology seen in 18% of young MMC urbanites obligate us to revise the dementia numbers in Mexico and Latin America (LA) and the prevalence of frontotemporal dementia (FTD). 172,173,162 Custodio et al 172 discussed LA prevalence of dementia reaching 7.1%, with AD being the most frequent type. FTD cases range from 12 to 18 cases per 1000 people with significant differences among Brazilians > Peruvians>Venezuelans.…”

Section: Discussionmentioning

confidence: 99%

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal

Calderón‐Garcidueñas

González-Maciel

Reynoso-Robles

et al. 2020

Environmental Research

143

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Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases. AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29±11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al-and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) likely key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry,thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breath, what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

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Section: Discussionmentioning

confidence: 99%

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal

Calderón‐Garcidueñas

González-Maciel

Reynoso-Robles

et al. 2020

Environmental Research

143

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“…ALS is at least two centuries old and is a rare, relentless, multi-layered and heterogeneous familial/sporadic disease targeting motor neurons and additional cell phenotypes as muscles, glia and immune cells (Casterton et al, 2020;Yerbury et al, 2020). It typically causes death within 3-5 years from onset, but it still has no cure because all efforts in the search for treatments have failed so far (Mejzini et al, 2019;Chiò et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Duality of P2X7 Receptor in Amyotrophic Lateral Sclerosis

et al. 2020

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“…For instance, mutations of the C9orf72 (Chromosome 9 open reading frame 72) gene have been shown to affect the activity of Rab protein, with the induction of endo-lysosomal pathway dysfunction, altered autophagy, and accumulation of protein aggregates in ALS-FTD1 [ 62 ]. Mutations in the genes UBQLN2 (ubiquilin-2), VCP (valosin-containing protein), OPTN (optineurin), TBK1 (serine/threonine-protein kinase-TBK1), respectively cause of ALS15, ALS14, ALS12, ALS-FTD4, are also associated with the lysosomes and autophagy impairment [ 64 ]. Moreover, lysosomal dysfunction, or/and the associated autophagic pathways, are also described in the other ALS forms [ 4 , 58 , 59 , 60 , 61 ], however, the precise effect in the pathogenesis of ALS is still controversial and is under extensive exploration.…”

Section: Discussionmentioning

confidence: 99%

Storage of Mutant Human SOD1 in Non-Neural Cells from the Type-1 Amyotrophic Lateral Sclerosis ratG93A Model Correlated with the Lysosomes’ Dysfunction

et al. 2021

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Herein, we explored the impact of the lysosome dysfunction during the progression of Amyotrophic Lateral Sclerosis type-1 (ALS1). We conducted the study in non-neural cells, primary fibroblasts (rFFFs), and bone marrow-mesenchymal stem cells (rBM-MSCs), isolated from the animal model ratG93A for ALS1 at two stages of the disease: Pre-symptomatic-stage (ALS1-PreS) and Terminal-stage (ALS1-EndS). We documented the storage of human mutant Superoxide Dismutase 1, SOD1G93A (SOD1*) in the lysosomes of ALS1-rFFFs and ALS1-rBM-MSCs and demonstrated the hallmarks of the disease in non-neural cells as in ratG93A-ALS1-tissues. We showed that the SOD1* storage is associated with the altered glycohydrolases and proteases levels in tissues and both cell types from ALS1-PreS to ALS1-EndS. Only in ALS1-rFFFs, the lysosomes lost homeostasis, enlarge drastically, and contribute to the cell metabolic damage. Contrariwise, in ALS1-rBM-MSCs, we found a negligible metabolic dysfunction, which makes these cells’ status similar to WT. We addressed this phenomenon to a safety mechanism perhaps associated with an enhanced lysosomal autophagic activity in ALS1-rBM-MSCs compared to ALS1-rFFFs, in which the lysosomal level of LC3-II/LC3I was comparable to that of WT-rFFFs. We suggested that the autophagic machinery could balance the storage of SOD1* aggregates and the lysosomal enzyme dysfunction even in ALS1-EndS-stem cells.

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Pathomechanism Heterogeneity in the Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disease Spectrum: Providing Focus Through the Lens of Autophagy

Cited by 24 publications

References 209 publications

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal

Duality of P2X7 Receptor in Amyotrophic Lateral Sclerosis

Storage of Mutant Human SOD1 in Non-Neural Cells from the Type-1 Amyotrophic Lateral Sclerosis ratG93A Model Correlated with the Lysosomes’ Dysfunction

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