Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7

Abstract

Huntington's disease (HD) is caused by an expansion of a polyglutamine repeat of more than 35 units in the huntingtin protein. The expanded repeat length is inversely correlated with the age at onset (AAO); however, additional genetic factors apart from the expanded CAG repeat length can modify the course and the AAO in HD. Aberrations in macroautophagy have been observed in Huntington, Alzheimer, Parkinson, motor neuron and prion diseases. Therefore, we hypothesized that polymorphisms in autophagy-related (Atg) genes might contribute to the variation in the AAO. We initially tested eight single nucleotide polymorphisms in five Atg genes (Atg3, Atg5, Atg7, Atg16L1 and Beclin-1) for their frequency of ≥1%. Subsequently, we investigated the polymorphisms Atg7 V471A and Atg16L1 T281A for a disease-modifying effect in more than 900 European HD patients (including 2 populations consisting of 346 German patients and 327 patients of Italian descent). One polymorphism in the Atg7 gene that substitutes alanine for valine (V471A) showed a significant effect on the AAO (P=0.0050) and was associated with an earlier disease onset of 4 years. Our results further support the important pathophysiological role of autophagy in HD.

Autophagy and neurodegeneration

“…While it is not yet clear whether alterations in autophagy are primary factors in the pathogenesis of HD, polymorphisms in the core autophagy gene, ATG7, have been suggested to be associated with earlier age of onset (76).…”

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

“…In particular, autophagy inhibition leads to polyubiquitin aggregate accumulation (Rubinsztein, 2006), and certain genetic changes in neurodegenerative disorders identify autophagy genes. For example, the age of onset in Huntington's disease is modified by a polymorphism in autophagy gene ATG7 (Metzger et al, 2010), and an α-synuclein variant that is causal for Parkinson's disease impairs autophagy through beclin 1 inhibition (Yan et al, 2014). Furthermore, autophagy-deficient mouse neurons accumulate polyubiquitin aggregates and exhibit neurodegeneration (Komatsu et al, 2006(Komatsu et al, , 2007.…”

Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

“…In HD models aberrant cargo recognition, as well as alterations of autophagic flux, has been reported (Heng et al, 2010;Martinez-Vicente et al, 2010). Furthermore, a polymorphism in the autophagy-related gene 7 (Atg7) was recently shown to influence the age-of-onset in HD patients (Metzger et al, 2010). However, not much is known about how other polyglutamine proteins affect the autophagy process.…”