Dissecting the effects of GTPase and kinase domain mutations on LRRK2 endosomal localization and activity

Rinaldi, Capria; Waters, Christopher S.; Li, Zizheng; Kumbier, Karl; Rao, Lee; Nichols, R. Jeremy; Jacobson, Matthew P.; Wu, Lani F.; Altschuler, Steven J.

doi:10.1016/j.celrep.2023.112447

Cited by 3 publications

(1 citation statement)

References 70 publications

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“…These findings suggest that an imbalance between hyperphosphorylated Rabs and ARF6 disrupts the proper transport of autophagosomes, potentially contributing to the development of PD. Third study demonstrated that inhibition of endosomal maturation leads to rapid formation of GTPase-inactivating mutants LRRK2 + endosomes, where LRRK2 phosphorylates its substrate Rabs (Rinaldi et al 2023 ). These LRRK2 + endosomes are sustained through positive feedback, reinforcing the membrane localization of both LRRK2 and phosphorylated Rab substrates.…”

Section: Vesicular Transport Factors In Pd Pathogenesismentioning

confidence: 99%

Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein

Matsui,

Takahashi

2024

J Neural Transm

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature of PD is the abnormal accumulation of α-synuclein protein within affected neurons, manifesting as Lewy bodies and Lewy neurites. Despite extensive research efforts spanning several decades, the underlying mechanisms of PD and disease-modifying therapies remain elusive. This review provides an overview of current trends in basic research on PD. Initially, it discusses the involvement of mitochondrial dysfunction in the pathogenesis of PD, followed by insights into the role of lysosomal dysfunction and disruptions in the vesicular transport system. Additionally, it delves into the pathological and physiological roles of α-synuclein, a crucial protein associated with PD pathophysiology. Overall, the purpose of this review is to comprehend the current state of elucidating the intricate mechanisms underlying PD and to outline future directions in understanding this disease.

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Section: Vesicular Transport Factors In Pd Pathogenesismentioning

confidence: 99%

Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein

Matsui,

Takahashi

2024

J Neural Transm

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Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation

Fasiczka

Naaldijk

Brahmia

et al. 2023

Biochemical Society Transactions

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Point mutations in leucine-rich repeat kinase 2 (LRRK2) which cause Parkinson's disease increase its kinase activity, and a subset of Rab GTPases have been identified as endogenous LRRK2 kinase substrates. Their phosphorylation correlates with a loss-of-function for the membrane trafficking steps they are normally involved in, but it also allows them to bind to a novel set of effector proteins with dominant cellular consequences. In this brief review, we will summarize novel findings related to the LRRK2-mediated phosphorylation of Rab GTPases and its various cellular consequences in vitro and in the intact brain, and we will highlight major outstanding questions in the field.

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Tumorigenic and tumoricidal properties of exosomes in cancers; a forward look

Abbasi-Malati,

Azizi,

Milani

et al. 2024

Cell Commun Signal

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In recent decades, emerging data have highlighted the critical role of extracellular vesicles (EVs), especially (exosomes) Exos, in the progression and development of several cancer types. These nano-sized vesicles are released by different cell lineages within the cancer niche and maintain a suitable platform for the interchange of various signaling molecules in a paracrine manner. Based on several studies, Exos can transfer oncogenic factors to other cells, and alter the activity of immune cells, and tumor microenvironment, leading to the expansion of tumor cells and metastasis to the remote sites. It has been indicated that the cell-to-cell crosstalk is so complicated and a wide array of factors are involved in this process. How and by which mechanisms Exos can regulate the behavior of tumor cells and non-cancer cells is at the center of debate. Here, we scrutinize the molecular mechanisms involved in the oncogenic behavior of Exos released by different cell lineages of tumor parenchyma. Besides, tumoricidal properties of Exos from various stem cell (SC) types are discussed in detail.

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Dissecting the effects of GTPase and kinase domain mutations on LRRK2 endosomal localization and activity

Cited by 3 publications

References 70 publications

Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein

Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein

Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation

Tumorigenic and tumoricidal properties of exosomes in cancers; a forward look

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