Misfolded proteinase K–resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies

Abstract

The pathological modifications of α-synuclein (αS) in Parkinson disease and related diseases are poorly understood. We have detected misfolded αS in situ based on the proteinase K resistance (PK resistance) of αS fibrils, and using specific antibodies against S129-phosphorylated αS as well as oxidized αS. Unexpectedly massive neuritic pathology was found in affected human brain regions, in addition to classical αS pathology. PK resistance and abnormal phosphorylation of αS developed with increasing age in (Thy1)-h[A30P] αS transgenic mice, concomitant with formation of argyrophilic, thioflavin S-positive, and electron-dense inclusions that were occasionally ubiquitinated. αS pathology in the transgenic mice was predominantly in the brainstem and spinal cord. Astrogliosis was found in these heavily affected tissues. Homozygous mice showed the same pathology approximately one year earlier. The transgenic mice showed a progressive deterioration of locomotor function

Spinal cord and parkinsonism: Neuromorphological evidences in humans and experimental studies

“…This severe clinical phenotype occurs earlier in the disease in the homozygous transgenic mice, whereas in the heterozygous is present only in later stages Lee et al, 2002;Gomez-Isla et al, 2003), indicating that increased levels of mutant a-Syn, expressed in homozygous transgenic mice are crucial to drive nerve fibers' degeneration and motoneurons disease. Similar pathological alterations were detected in human A30P a-Syn transgenic mice that develop a neurodegenerative phenotype with age-dependent penetrance, characterized by rapidly deteriorating motor performance, with hind limbs paralysis (Neumann et al, 2002;Fournier et al, 2009). In both transgenic models these pathological features develop in absence or before degeneration of nigral dopaminergic neurons.…”

The regulatory role of α-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson’s disease

“…These models exhibited abnormal accumulation of aSyn protein in neurons and altered behavioral phenotypes. However, these animals hardly displayed progressive loss of DA neurons in the SNpc [4,[85][86][87][88][89][90][91][92][93][94][95]. Among these, Masliah et al (2000) showed inclusion formation and significant reduction of DA nerve terminals in the striatum of the aSyn-transgenic mice [85].…”

Physiological and pathological properties of α-synuclein

“…In studies using the mPrP promoter and contrary to earlier reports, no abnormal a-synuclein accumulation or behavioural deficits were detected in mice overexpressing the WT human protein. Transgenic mice overexpressing the A30P mutant a-synuclein driven by the Thy1 promoter also develop many of the salient features of LB disease such as proteinase Kresistance, neuritic pathology and formation of some argyrophilic and thioflavin S-positive a-synuclein inclusions with increasing age [45]. It is of interest that although mPrP but not Thy1 promoter drives high expression of the transgene in neurones of the substantia nigra (SN), as revealed by in situ hybridisation [44], the tyrosine hydroxylase (TH)-positive neurones of the SN in the mPrP-driven transgenic mice were completely spared from asynuclein aggregates or other deficits such as loss of striatal dopamine or dopamine transporter [43,44].…”