Mutation in TECPR2 Reveals a Role for Autophagy in Hereditary Spastic Paraparesis

Abstract

We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy. We thus examined the autophagy-related fate of two key autophagic proteins, SQSTM1 (p62) and MAP1LC3B (LC3), in skin fibroblasts of an affected individual, as compared to a healthy control, and found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II). siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy. Our results are strengthened by the fact that autophagy dysfunction has been implicated in a number of other neurodegenerative diseases. The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis.

Autophagy and human diseases

“…Skin fibroblasts from an HSP patient showed decreased autophagic flux, but no accumulation of the autophagic substrate SQSTM1/p62, implying that some autophagic activity could be maintained in affected individuals. Knockdown of TECPR2 in HeLa cells also reduced autophagic activity, suggesting that TECPR2 is a bona fide autophagy factor [35]. However, the exact role of TECPR2 in the autophagy pathway warrants further examination.…”

“…It leads to progressive spasticity and hyperreflexia of the lower limbs [36][37][38]. The newly characterized HSP subtype, accompanied by lower-limb spasticity and other neurological symptoms, appears to be an autosomalrecessive form of complicated HSP that is caused by a single base deletion in the TECPR2 gene, resulting in a premature stop codon accompanied by full degradation of its protein product [35].…”

“…However, the exact role of TECPR2 in the autophagy pathway warrants further examination. The fact that TECPR2 shows some similarity to two autophagy-involved proteins -TECPR1 and HPS5 [35,[40][41][42][43] -is expected to shed new light on this issue.…”

“…Oz-Levi et al reported a recessive mutation in TECPR2, an autophagy-related WD repeat-containing protein, in five individuals with SPG49, a novel form of recessive hereditary spastic paraparesis (HSP) [35]. HSP is a diverse group of neurodegenerative disorders characterized by axonal degeneration of the corticospinal or pyramidal motor and sensory tracts that control the lower extremities.…”

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

“…Mutations in the autophagy gene WDR45 have been associated with static encephalopathy of childhood with generation in adulthood (SENDA), and SENDA disease phenotypes (iron accumulation and cerebral atrophy) appear to be restricted to the brain despite WDR45 expression in skeletal muscle (7). Brain-related disease phenotypes have also been observed in patients with a form of hereditary spastic paraparesis bearing a recessive mutation in the putative autophagy regulator TECPR2, and in patients suffering from cerebellar atrophy associated with mutations in the autophagy modulator SNX14 (8,9).…”