Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.

Early low-dose ghrelin intervention via mini-osmotic pumps could protect against the progressive dopaminergic neuron loss in Parkinson’s disease mice

BackgroundGhrelin has been identified as a multifunctional peptide that has a potential applications for the treatment Parkinson’s disease (PD). Method: ELISA was used for detecting plasma total and active ghrelin levels, dopamine (DA) content was measured by HPLC-ECD, immunofluorescence staining and Western blot were used to detect protein expressions, and cytokine was tested by Bio-PlexPro™ assay.ResultsHere, we reported a subcutaneous administration of low-dose ghrelin via mini-osmotic pumps to PD mice. The decreased levels of total and active ghrelin in plasma were rescued by ghrelin administration. Interestingly, ghrelin had no effect on weight gain in wild-type mice but improved weight loss in PD mice. We observed the attenuation of dopaminergic (DAergic) neuron loss in substantia nigra (SN) and low level of dopamine content in the striatum in PD mice with ghrelin treatment. Ghrelin administration could improve the environment of DAergic neuron by inhibiting microglia proliferation and pro-inflammatory cytokine expression, and could enhance cell survival by upregulating Bcl-2/Bax ratio and superoxide dismutase1 (SOD1) protein level in SN in PD mice.ConclusionsOur results suggested that subcutaneous administration of low-dose ghrelin could prevent the onset or the progression of PD, and also provided a possible method for ghrelin application to cure PD.

Haploinsufficiency of Parkinsonism Gene SYNJ1 Contributes to Dopamine neuron Vulnerability in Aged Mice

Parkinson’s disease (PD) is an age-dependent neurodegenerative disorder characterized by the loss of substantia nigra dopaminergic (DAergic) neurons in ventral midbrain (MB). Identification of interactions between aging and the known risk variants is crucial to understanding the etiology of PD. Recessive mutations in SYNJ1 have recently been linked to familial early-onset atypical Parkinsonism. We now show an age-dependent decline of SYNJ1 expression in the striatum as well as in striatal DAergic terminals of aged mice. Heterozygous deletion of SYNJ1 in mice causes selective elevation of PIP2 in the MB, and manipulation of PIP2 levels also impairs synaptic vesicle recycling preferentially in MB neurons. SYNJ1+/− mice display progressive PD-like behavioral alterations and DAergic terminal degeneration. Furthermore, we found down-regulation of human SYNJ1 transcripts in a subset of sporadic PD brains, corroborating the role of an age-dependent decrease in SYNJ1 in predisposing DAergic neuron vulnerability and PD pathogenesis.