Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice

TLDR

Mutations in α‑synuclein cause familial Parkinson’s disease, and its accumulation forms Lewy bodies and neurites, hallmark inclusions of the disease. The study aimed to elucidate how α‑synuclein variants drive Parkinson’s‑associated neurodegeneration by creating transgenic mice expressing wild‑type, A30P, or A53T human α‑synuclein. Transgenic mice were engineered to overexpress human α‑synuclein variants (wild‑type, A30P, A53T) at high levels. Only the A53T transgenic mice developed adult‑onset neurodegenerative disease with progressive motor dysfunction and death, accompanied by neuronal abnormalities, α‑synuclein and ubiquitin inclusions, increased detergent‑insoluble α‑synuclein aggregates, and greater neurotoxicity compared to other variants.

Abstract

Mutations in α-synuclein (α-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, α-Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of α-Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 → Pro (A30P) or Ala-53 → Thr (A53T) human α-Syns. The mice expressing the A53T human α-Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of α-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of α-Syn, brain regions with pathology exhibit increases in detergent-insoluble α-Syn and α-Syn aggregates. Our results demonstrate that the A53T mutant α-Syn causes significantly greater in vivo neurotoxicity as compared with other α-Syn variants. Further, α-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble α-Syn.