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LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a
Drp1-STX17-dependent manner
#MMPMID41354840
Ding M
; Wang F
; Jiang LL
; Ma C
; Qi YW
; Liu JY
; Li J
; Wang MX
; Jin H
; Zhang JR
; Mao CJ
; Li XK
; Liu CF
; Cheng XY
Transl Neurodegener
2025[Dec]; 14
(1
): 64
PMID41354840
show ga
BACKGROUND: Previous studies have shown that astrocytes can transfer healthy
mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic
neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most
common pathogenic mutation associated with PD. In this study, we explored whether
mitochondrial transfer is influenced by genetic and environmental factors and
whether dysfunction in this process is one of the mechanisms of the pathogenic
LRRK2 G2019S mutation. METHODS: DA neurons and astrocytes were differentiated
from induced pluripotent stem cells generated from the peripheral blood of a
healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A
coculture system of astrocytes and DA neurons was established to explore the
pathogenic mechanisms of LRRK2 G2019S. RESULTS: Exposure to the environmental
toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons.
Compared with the co-culture system from the healthy participant, the co-culture
system harboring the LRRK2 G2019S mutation experienced more pronounced damage.
Specifically, STX17 was colocalized with the mitochondrial outer membrane marker
TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted
with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased
phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of
colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor
DUSP6 restored the colocalization of STX17 and TOM20, as well as
the mitochondrial transfer efficiency and neuronal survival. CONCLUSIONS: The
impairment of mitochondrial transfer is a potential pathogenic mechanism
associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial
transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably,
inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through
mitigating mitochondrial transfer impairments. This study provides novel insights
into the pathogenesis of PD and the development of new therapeutic targets.
|*Dopaminergic Neurons/metabolism
[MESH]
|*Dynamins/metabolism/genetics
[MESH]
|*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/metabolism
[MESH]
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