Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

• Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (alpha-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects alpha-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in alpha-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary alpha-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated alpha-syn for 24 h and analyzed directly after the alpha-syn pulse or 6 days later. To elucidate the impact of LRRK2 on alpha-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar alpha-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of alpha-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular alpha-syn aggregates through an AnxA2-dependent mechanism.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

Parkinson's disease

alpha-Synuclein

LRRK2

Astrocytes

Glia

Neurodegeneration

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)