P62 Gene Mutations Are Causally Related to Amyotrophic Lateral Sclerosis
Yes, mutations in the SQSTM1 gene encoding p62 protein are definitively associated with both familial and sporadic ALS, representing a direct genetic cause in a subset of patients. Multiple independent research studies have identified pathogenic SQSTM1 mutations in ALS patients across different populations, with neuropathological confirmation showing characteristic p62-positive inclusions in degenerating motor neurons 1, 2.
Genetic Evidence for P62 in ALS
SQSTM1 mutations have been identified in both familial ALS (FALS) and sporadic ALS (SALS) patients, with mutations found in approximately 1-3% of ALS cases across multiple cohorts 1, 2, 3
A comprehensive screening of 546 ALS patients (340 familial, 206 sporadic) identified 10 novel SQSTM1 mutations in 15 patients, with in silico analysis classifying 8 of 9 missense variants as pathogenic 2
Mutations occur throughout the SQSTM1 gene, including the ubiquitin-associated domain (UBA domain) in exon 8, as well as novel mutations in exons 2 and 3 1
The p.Pro392Leu mutation in the UBA domain has been identified in multiple ALS patients, some with concomitant Paget's disease of bone 1
Novel mutations identified include p.Met87Val, p.Lys102Glu, p.Ala53Thr, and p.Pro439Leu, which were absent in control populations 1, 3
Neuropathological Confirmation
Autopsy examination of ALS patients with SQSTM1 mutations reveals characteristic large round p62-positive inclusions in motor neurons, distinct from typical TDP-43 pathology 1, 4
Immunoblot analysis demonstrates increased p62 and TDP-43 protein levels in the spinal cord of mutation carriers 1
Selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in lower motor neurons is a characteristic feature of SQSTM1-related ALS 4
Ultrastructural examination shows p62-positive inclusions composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures in spinal anterior horn cells 4
Notably, Bunina bodies (a typical ALS pathological feature) were absent in at least one case with compound heterozygous SQSTM1 mutations 4
Clinical Presentation
The clinical picture of SQSTM1 mutation-positive patients is typical ALS with varied upper motor neuron signs, indistinguishable from other ALS cases 3
Patients present with both familial and sporadic patterns, with late-onset disease possible 4, 3
Some patients with SQSTM1 mutations have concomitant Paget's disease of bone, though this is not universal 1, 3
The mutations show worldwide distribution, having been identified in French, American, and Japanese populations 1, 2, 3
Compound Heterozygous Mutations
A case of sporadic ALS with compound heterozygous SQSTM1 mutations (p.[Val90Met];[Val153Ile]) has been documented, suggesting that biallelic mutations may also contribute to disease 4
This case demonstrated distinct p62 pathology in lower motor neurons with concomitant Lewy body pathology, indicating potential overlap with other neurodegenerative processes 4
Overlap with Frontotemporal Lobar Degeneration
SQSTM1 mutations are also found in frontotemporal lobar degeneration (FTLD) patients, supporting the genetic overlap between ALS and FTLD 5
Six missense mutations in the coding region were identified in FTLD or ALS patients, none of which were found in healthy controls or Paget's disease patients 5
Seven novel noncoding SQSTM1 variants were identified, including four variations in the promoter region 5
Pathogenic Mechanism
P62 is a multifunctional adapter protein involved in selective autophagy, oxidative stress response, and cell signaling pathways 5
The protein is a major component of ubiquitin inclusions detected in degenerating neurons in ALS patients 1
Mutations in SQSTM1 disrupt protein degradation pathways, suggesting this represents an important therapeutic target in motor neuron degeneration 2
Clinical Implications
Genetic testing for SQSTM1 mutations should be considered in both familial and sporadic ALS cases, particularly when family history is unclear or when patients have concomitant Paget's disease 1, 2
The identification of SQSTM1 mutations provides evidence for a direct genetic role of p62 in ALS pathogenesis 2
Regulation of protein degradation pathways may represent an important therapeutic target in SQSTM1-related ALS 2
The presence of distinct p62 pathology in lower motor neurons indicates the pathogenic role of SQSTM1 mutations in developing a subset of ALS 4