The accumulation of abnormal α-synuclein is the major histopathological feature 
of Lewy body disease and multiple system atrophy (MSA), which are referred to as 
synucleinopathies. Cytoplasmic degradation systems, such as the 
autophagy-lysosome and proteasome pathways, are involved in their pathogenesis. 
Autophagy is tightly regulated by several upstream proteins including 
UNC-51-like kinase 1/2, beclin1, vacuolar protein sorting-associated protein 34 
and autophagy/beclin1 regulator 1 (AMBRA1). Recently, we revealed that both 
cortical and brainstem-type Lewy bodies were immunopositive for several upstream 
proteins of autophagy. Therefore, we conducted the present study to elucidate 
the role of upstream proteins of autophagy in the pathogenesis of MSA. 
Pathological and biochemical analyses using human brain samples revealed that 
AMBRA1 is a component of the pathological hallmarks of MSA and upstream proteins 
of autophagy are impaired in the MSA brain. In vitro and in vivo analyses 
revealed a ninefold stronger affinity of AMBRA1 with α-synuclein phosphorylated 
at serine 129 compared with non-phosphorylated α-synuclein. Furthermore, a weak 
but significant correlation between AMBRA1 overexpression and reduction of 
abnormal α-synuclein was observed. Silencing AMBRA1 function caused aggregates 
of α-synuclein in the cytoplasm of mouse primary cultured neurons, which was 
simulated by the treatment of Bafilomycin, an autophagy inhibitor. Our results 
demonstrated for the first time that AMBRA1 is a novel hub binding protein of 
α-synuclein and plays a central role in the pathogenesis of MSA through the 
degradative dynamics of α-synuclein. These results raise the possibility that 
molecular modulation targeting AMBRA1 can be a promising candidate for the 
treatment of synucleinopathies.