28 March 23

Our new paper on Parkinson’s disease

We evaluated the neuroprotective role of a novel target against alpha-synuclein neuropathology and elucidated its role in the autophagy-lysosome pathway. We validated the potential of the small GTPase Rit2 in vitro and in vivo models.

  • English

In Parkinson’s disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear, but they are hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, and LRRK2 kinase activity has been shown to be involved in pS129-aSyn inclusion modulation.

Enhanced Rit2 expression in the mouse midbrain counteracts aSyn-dependent deficits and DA neuron loss. c: IHC for TH was used to count dopaminergic neurons in the midbrain. d: Overexpression of A53T-aSyn alone induces a significant loss of DA neurons, which is attenuated by co-injection of AAV-Rit2.

We observed selective downregulation of the novel PD risk factor RIT2 in vitro and in vivo. Rit2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of Rit2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, Rit2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. On the other hand, reduction of Rit2 levels leads to defects in the ALP, similar to those induced by the G2019S-LRRK2 mutation. Our data indicate that Rit2 is required for correct lysosome function, inhibits overactive LRRK2 to ameliorate ALP impairment, and counteracts aSyn aggregation and related deficits. Targeting Rit2 could represent an effective strategy to combat neuropathology in familial and idiopathic PD.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 2–3% of people over the age of 65. The disease is characterized by motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability, which originate from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Around 15% of PD patients have a family history and 5–10% of cases are caused by mutations and alterations in specific genes (e.g., SNCA, LRRK2, Parkin, VPS35).

Read the full article here: https://www.nature.com/articles/s41531-023-00484-2

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