bims-midbra 2022-01-30 papers

Issue of 2022–01–30
three papers selected by
Ana Paula Mendonça, University of Padova

Transl Neurodegener. 2022 Jan 25. 11(1): 3

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.

Manish Verma, Britney N Lizama, Charleen T Chu.

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Beta-amyloid; Excitotoxicity; Glucocerebrosidase; Huntington’s disease; LRRK2; Mitochondrial calcium; Mitochondrial calcium uniporter; Mitophagy; NCLX antiporter; PINK1; Parkinson’s disease

DOI: https://doi.org/10.1186/s40035-021-00278-7

Eur J Neurosci. 2022 Jan 25.

Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's Disease.

Arpita Bera, Gantyada Lavanya, Ravada Reshmi, Kapil Dev, Rahul Kumar.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, has emerged as the most common form of dementia in the elderly. Two major pathological hallmarks have been identified for AD; extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Recently, dynamin-related protein 1 (Drp1) was recognized to contribute significantly towards the pathogenesis of AD. Drp1 is primarily located in the cytosol, from where it translocates to the mitochondrial outer membrane and drives the mitochondrial fission via GTP hydrolysis. Drp1 interacts with Aβ and phosphorylated tau, leading to excessive mitochondrial fragmentation, which in turn results in synaptic dysfunction, neuronal damage, and cognitive decline. Several studies suggest an increase in the level of Drp1 in the post-mortem brain specimen collected from the AD patients and murine models of AD. Interestingly, heterozygous deletion of Drp1 in the transgenic murine model of AD ameliorates the mitochondrial dysfunction, improves learning and memory. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of AD. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for AD in the future.

Keywords: Drp1; Mitophagy; Neurodegeneration; Neurofibrillary tangles; Tau phosphorylation; amyloid plaques

DOI: https://doi.org/10.1111/ejn.15611

Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01699-5. [Epub ahead of print]38(4): 110195

Disrupted autophagy and neuronal dysfunction in C. elegans knockin models of FUS amyotrophic lateral sclerosis.

Saba N Baskoylu, Natalie Chapkis, Burak Unsal, Jeremy Lins, Kelsey Schuch, Jonah Simon, Anne C Hart.

How mutations in FUS lead to neuronal dysfunction in amyotrophic lateral sclerosis (ALS) patients remains unclear. To examine mechanisms underlying ALS FUS dysfunction, we generate C. elegans knockin models using CRISPR-Cas9-mediated genome editing, creating R524S and P525L ALS FUS models. Although FUS inclusions are not detected, ALS FUS animals show defective neuromuscular function and locomotion under stress. Unlike animals lacking the endogenous FUS ortholog, ALS FUS animals have impaired neuronal autophagy and increased SQST-1 accumulation in motor neurons. Loss of sqst-1, the C. elegans ortholog for ALS-linked, autophagy adaptor protein SQSTM1/p62, suppresses both neuromuscular and stress-induced locomotion defects in ALS FUS animals, but does not suppress neuronal autophagy defects. Therefore, autophagy dysfunction is upstream of, and not dependent on, SQSTM1 function in ALS FUS pathogenesis. Combined, our findings demonstrate that autophagy dysfunction likely contributes to protein homeostasis and neuromuscular defects in ALS FUS knockin animals.

Keywords: ALS; C. elegans; FUS; autophagy

DOI: https://doi.org/10.1016/j.celrep.2021.110195