Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson’s disease-like motor impairments

TL;DR

Reducing HSPA9 in mice leads to loss of dopamine-producing neurons and Parkinson's-like symptoms, suggesting HSPA9 may play a role in Parkinson's disease.

Contribution

This study demonstrates that HSPA9 haploinsufficiency causes PD-like neuronal loss and motor impairments in mice.

Findings

Hspa9 haploinsufficiency leads to loss of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum.

Hspa9 deficiency causes mitochondrial fission, increased apoptosis, and worsened motor performance in mice.

MPTP treatment in Hspa9+/− mice worsens dopaminergic neuron loss and activates caspase-3.

Abstract

Parkinson’s disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer’s disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9+/−) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9+/− mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.

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