Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Abstract

SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

“…More recently, homozygous loss of function mutations in p62 were identified in patients with childhood onset neurodegeneration (Haack et al, 2016). Some p62 disease mutations reside within or lead to premature truncations of the UBA domain (Rea et al, 2014).…”

Metabolic regulation of neurodifferentiation in the adult brain

“…P62 is a cytosolic, multi-domain protein, considered to be involved in, among others, selective autophagy [108]. Patients with bi-allelic null mutations in p62 present with childhood-or adolescence-onset neurodegenerative disorder, characterised by progressive gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline [109,110]. Loss of p62 in NES cells resulted in a dramatic increase of LDHA expression, which correlated with deficient neurodifferentiation [99].…”

p62 filaments capture and present ubiquitinated cargos for autophagy

“…The major cargo receptor for aggrephagy is p62/SQSTM1 (Stolz et al , ). Mutations in the SQSTM1 gene have been associated with several diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FD), and neurodegeneration with ataxia (Fecto et al , ; Rubino et al , ; Goode et al , ; Haack et al , ). p62 binds to ubiquitin via its C‐terminal UBA domain and to ATG8 proteins, including LC3B, through an LC3‐interacting region (LIR) located in an intrinsically disordered region (Fig A; Seibenhener et al , ; Pankiv et al , ).…”