LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson's disease

Chang, Eunice Eun Seo; Ho, Philip Wing-Lok; Liu, Huifang; Pang, Shirley Yin-Yu; Leung, Chi-Ting; Malki, Yasine; Choi, Zoe Yuen-Kiu; Ramsden, D.; Ho, Shu‐Leong

doi:10.1186/s40035-022-00285-2

Cited by 22 publications

(11 citation statements)

References 204 publications

(276 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the near complete protection against neurotoxicity in our experimental systems here, LRRK2-mediated effects cannot explain every pathological endpoint associated with environmental toxicants implicated in PD risk 65,66 . For example, we found that a threshold exists for LRRK2 protection against mitochondrial toxicity.…”

Section: Discussionmentioning

confidence: 70%

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

View full text Add to dashboard Cite

Idiopathic Parkinson′s disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk — rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant–induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

show abstract

Section: Discussionmentioning

confidence: 70%

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In other PD mouse models, including single knock-out (e.g. DJ-1, PINK1, PRKN), triple PINK1/PRKN/DJ-1 knock-out or LRKK2-R1441G transgenic mice, no dopaminergic neurodegeneration was observed albeit their motor coordination is altered [63][64][65][66]. Herein, we showed that physiological levels of Miro1 with p.R285Q mutation led to behavior impairments and SNpc TH loss in an age-dependent way.…”

Section: Discussionmentioning

confidence: 70%

Parkinson’s disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neuronsin vitroandin vivo

Chemla,

Arena,

Sacripanti

et al. 2023

Preprint

View full text Add to dashboard Cite

The complex and heterogeneous nature of Parkinson’s disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairments as a major driver of neurodegeneration in PD. Recently, the regulator of mitochondrial homeostasis Miro1 has been linked genetically and pathophysiologically to PD. Using 2D and 3D patient-based induced pluripotent stem cells models, including an isogenic control, showed that the Miro1 p.R272Q mutation leads to mitochondrial impairments including increased oxidative stress, disrupted mitochondrial bioenergetics and altered metabolism. This was accompanied by increased α-synuclein levels in 2D dopaminergic neurons and by a significant reduction of dopaminergic neurons within midbrain organoids. Knock-in mice expressing mutant p.R285Q Miro1 (orthologue of the human p.R272Q mutation) confirmed the PD-specific dopaminergic neuronal loss in the substantia nigra, accumulation of striatal phosphorylated α-synuclein accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypesin vitroandin vivo, reinforcing its pivotal role in PD pathogenesis.

show abstract

“…Future studies investigating how phosphorylated and unphosphorylated states of EZRIN control astrocyte morphogenesis through modulation of the cytoskeleton will be helpful in deciphering mechanisms of astrocyte morphogenesis. LRRK2 G2019S ki/ki mice do not recapitulate cardinal motor symptoms of PD because there is no detectable dopaminergic neuron loss in these mice [67][68][69] . LRRK2 mutation carriers show non-motor symptoms in comparison to non-carriers, such as hyposmia and decreased cognitive performance 150 41,151,152 .…”

Section: Lrrk2 G2019s Mutation Disrupts Excitatory and Inhibitory Syn...mentioning

confidence: 98%

“…PD patients with the LRRK2 G2019S mutation also have non-motor symptoms, such as depression, hallucinations, and sleep and cognitive disorders 43,57,66 . Several rodent models with LRRK2 G2019S mutation have been generated; however, these models do not show motor dysfunction or dopaminergic neuron loss [67][68][69] . However, non-motor symptoms such as cognitive dysfunction is common in PD, indicating impairments in numerous brain regions, including the cerebellar cortex 70,71 .…”

Section: Astrocytic Lrrk2 Controls Astrocyte Morphology Through Erm P...mentioning

confidence: 99%

Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation

Wang

Bindu

Tan

et al. 2023

Preprint

View full text Add to dashboard Cite

Astrocytes tightly control neuronal connectivity and function in the brain through direct contact with synapses. These glial cells become reactive during disease pathogenesis including Parkinson's disease (PD). However, it remains unknown if astrocyte dysfunction is an initiating factor of PD pathogenesis and whether astrocytes can be targeted to stop or reverse the synaptic dysfunction seen in PD. Using in vitro and in vivo methods, we found that the PD-linked gene Lrrk2 controls astrocyte morphology via regulating the phosphorylation of ERM proteins (Ezrin, Radixin, and Moesin), a structural component of the perisynaptic astrocyte processes. ERM phosphorylation is robustly elevated both in mice and humans carrying the LRRK2 G2019S Parkinsonism mutation. Importantly, the reduction of the ERM phosphorylation, specifically in the LRRK2 G2019S in adult astrocytes, is sufficient to restore excitatory synapse number and function deficits in the LRRK2 G2019S knock-in mouse cortex. These results show a role for Lrrk2 in controlling astrocyte morphogenesis and synaptogenic function and reveal that early astrocyte dysfunction in PD could be causal to disruptions in cortical excitatory synaptic connectivity. The astrocytic dysfunction can be corrected by dampening ERM phosphorylation, pinpointing astrocytes as critical cellular targets for PD therapeutics.

show abstract

LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson's disease

Cited by 22 publications

References 204 publications

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Parkinson’s disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neuronsin vitroandin vivo

Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation

Contact Info

Product

Resources

About