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Proteomic analysis of MetaAggregates in amyotrophic lateral sclerosis brains

ABSTRACT: RNA-binding proteins (RBPs) are key regulators of translation and have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Among candidate pathological entities are heterogeneous co-aggregates, or â€œMetaAggregates,â€ composed of amyloids, RBPs, and RNA G-quadruplexes (rG4s). To explore their molecular constituents, we developed a proteomic approach using a psoralen-conjugated RBP to crosslink with a biotinylated rG4, enabling isolation of MetaAggregates from ALS brain extracts. Single-cell RNA-seq of ALS iPS-derived neurons identified ELAVL4 as a cytoplasmic RNA-binding protein and revealed enrichment of an IGFBP2-derived rG4 structure in ALS-specific neurons. Label-free LC-MS/MS and amyloidogenicity-based principal component analysis revealed 79 candidate proteins with roles in RNA processing, metabolism, trafficking, and stress responses.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kazuma Murakami

PROVIDER: PXD065772 | JPOST Repository | Sat Jul 04 00:00:00 BST 2026

REPOSITORIES: jPOST

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Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from lower motor neurons obtained by laser capture microdissection from autopsy material from neurologically healthy controls (n=6) and cases of sporadic ALS (n=3) and ALS due to C9ORF72 mutations (n=3).

			Action	DRS
	1_ALS_1.raw	Raw
	2_ALS_2.raw	Raw
	3_ALS_3.raw	Raw
	4_ALS_control1.raw	Raw
	5_ALS_control2.raw	Raw

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Proteomic analysis of MetaAggregates in amyotrophic lateral sclerosis brains

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