Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

Abstract

ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

Hippocampal protein aggregation signatures fully distinguish pathogenic and wildtypeUBQLN2in amyotrophic lateral sclerosis

“…We previously exploited this to infer C9ORF72 repeat expansion genotypes [56,66] through neuropathological screening of our New Zealand ALS cases [38]. Mutant SOD1 [67,68], FUS [44], and certain other genotypes [69,70] can also be inferred from neuropathology. However, for many ALS/FTD genes -particularly those such as TARDBP, SQSTM1, and UBQLN2 that encode proteins already within the hallmark TDP-43 inclusions -no completely discriminating neuropathology has been reported [42,69,[71][72][73][74][75].…”

“…Mutant SOD1 [67,68], FUS [44], and certain other genotypes [69,70] can also be inferred from neuropathology. However, for many ALS/FTD genes -particularly those such as TARDBP, SQSTM1, and UBQLN2 that encode proteins already within the hallmark TDP-43 inclusions -no completely discriminating neuropathology has been reported [42,69,[71][72][73][74][75]. This has hampered the validation of pathogenicity of novel variants in these genes, in turn obscuring understanding of protein domains and molecular processes important to ALS/FTD pathogenesis.…”

“…The copyright holder for this preprint this version posted January 12, 2022. ; https://doi.org/10.1101/2022.01.12.475792 doi: bioRxiv preprint reported [42,69,[71][72][73][74][75]. This has hampered the validation of pathogenicity of novel variants in these genes, in turn obscuring understanding of protein domains and molecular processes important to ALS/FTD pathogenesis.…”

Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

“…A recent description of the human pathology of CHCHD10 p.R15L-ALS describes anterior horn neuronal CHCHD10-positive, TDP-43-negative protein aggregates ( Keith et al., 2020 ). Such aggregates are not apparent in the CHCHD10-R15L transgenic mice, but p62-positive, TDP-43-negative punctate staining is apparent in the spinal cord, indicating that the mice display some deficit in CNS protein degradation.…”

Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs)

“…In these cell types, SOD1 aggregates are found in the cytosol, but also within mitochondria, thus creating oxidative stress [ 41 , 42 ]. Other ALS gene products have been identified that produce proteins controlling mitochondrial protein import (coiled-coil-helix-coiled-coil domain protein 10, CHCHD10, [ 43 ]), the cytoskeleton (e.g., Profilin-1, ALS18 ), mRNA stability (e.g., Fused in sarcoma, FUS, ALS6 ), and protein trafficking (e.g., valosin-containing protein, VCP, ALS14 ) [ 44 , 45 ].…”