Identification of bilateral changes in TID1 expression in the 6-OHDA rat model of Parkinson's disease.

Juliane Proft,Gerlinde A Metz,Xiaoxi Zhao,Fabiola C R Zucchi,Janice E A Braun,Jerrah C Robbins,Jamshid Faraji,Mark R Cookson

doi:10.1371/journal.pone.0026045

Juliane Proft, Gerlinde A Metz + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0026045

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Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra and the aggregation of α-synuclein into Lewy bodies. Existing therapies address motor dysfunction but do not halt progression of the disease. A still unresolved question is the biochemical pathway that modulates the outcome of protein misfolding and aggregation processes in PD. The molecular chaperone network plays an important defensive role against cellular protein misfolding and has been identified as protective in experimental models of protein misfolding diseases like PD. Molecular mechanisms underlying chaperone-neuroprotection are actively under investigation. Current evidence implicates a number of molecular chaperones in PD including Hsp25, Hsp70 and Hsp90, however their precise involvement in the neurodegenerative cascade is unresolved. The J protein family (DnaJ or Hsp40 protein family) has long been known to be important in protein conformational processes.We assessed sensory and motor function of control and PD rats and then evaluated the brain region-specific expression levels of select J proteins by Western analysis. Surprisingly, we observed a widespread 26 kDa breakdown product of the J protein, TID1, (tumorous imaginal discs, mtHsp40 or DnaJ3) in a 6-hydroxydopamine (6-OHDA) rat model of PD in which food handling, gait symmetry and sensory performance were impaired. Greater behavioral deficits were associated with lower TID1 expression. Furthermore, direct application of either 6-OHDA or MPP+ (1-methyl-4-phenylpyridinum) to CAD (CNS-derived catecholinaminergic neuronal cell line) cell cultures, reduced TID1 expression levels.Our results suggest that changes in cellular TID1 are a factor in the pathogenesis of PD by impeding functional and structural compensation and exaggerating neurodegenerative processes. In contrast, no changes were observed in CSPα, Hsp40, Hsp70, Hsc70 and PrPC levels and no activation of caspase3 was observed. This study links TID1 to PD and provides a new target for therapeutics that halts the PD progression.

Highlights

In order to begin to understand the role that J proteins have in Parkinson’s disease (PD) we have evaluated the levels of select J proteins in a 6-OHDA rat model of PD
PD 6-OHDA lesion rats show severe sensorimotor deficits To begin to address the hypothesis that depletion of neural chaperones contributes to PD pathology, we have examined the levels of the J proteins TID1, CSPa and Hsp40 in the 6-OHDA rat model of PD
Administration of 6-OHDA, a toxic metabolite of dopamine found in the brain and urine of PD patients, is known to produce selective destruction of catecholaminergic neurons

Summary

Introduction

Parkinson’s disease (PD), a neurodegenerative disease that afflicts 1% of the population over 65, is characterized by degeneration of dopaminergic neurons in the substantia nigra and formation of intracytoplasmic -synuclein aggregates called Lewy bodies [1]. This change was specific to the J protein TID1 in that neither the stress-induced J protein, Hsp40 (heat shock protein of 40 kDa), nor the antineurodegenerative J protein, CSPa (cysteine string protein), expression levels were altered in PD rats.

Results

Conclusion