HMGA1 Induction of miR-103/107 Forms a Negative Feedback Loop to Regulate Autophagy in MPTP Model of Parkinson’s Disease

Abstract

Autophagy dysfunction has been directly linked with the onset and progression of Parkinson’s disease (PD), but the underlying mechanisms are not well understood. High-mobility group A1 (HMGA1), well-known chromatin remodeling proteins, play pivotal roles in diverse biological processes and diseases. Their function in neural cell death in PD, however, have not yet been fully elucidated. Here, we report that HMGA1 is highly induced during dopaminergic cell death in vitro and mice models of PD in vivo. Functional studies using genetic knockdown of endogenous HMGA1 show that HMGA1 signaling inhibition accelerates neural cell death, at least partially through aggravating MPP+-induced autophagic flux reduction resulting from partial block in autophagic flux at the terminal stages, indicating a novel potential neuroprotective role for HMGA1 in dopaminergic neurons death. MicroRNA-103/107 (miR-103/107) family, which is highly expressed in neuron, coordinately ensures proper end-stage autophagy. We further illustrate that MPP+/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced HMGA1 elevation counterparts the effect of miR-103/107 downregulation by directly binding to their promoters, respectively, sustaining their expression in MPP+-damaged MN9D cells and modulates autophagy through CDK5R1/CDK5 signaling pathway. We also find that HMGA1 is a direct target of miR-103/107 family. Thus, our results suggest that HMGA1 forms a negative feedback loop with miR-103/107-CDK5R1/CDK5 signaling to regulate the MPP+/MPTP-induced autophagy impairment and neural cell death. Collectively, we identify a paradigm for compensatory neuroprotective HMGA1 signaling in dopaminergic neurons that could have important therapeutic implications for PD.

Comparison of the effect of rotenone and 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine on inducing chronic Parkinson's disease in mouse models

“…The acute mouse model of PD has been created by injecting MPTP four times within 6 h ( 55 , 56 ). The subacute mouse PD model has been produced by injecting MPTP once a day for several days to several weeks ( 57 ). Finally, the chronic mouse model has been created by injecting MPTP and probenecid at 3.5-day intervals for 6 weeks.…”

microRNAs profiling of small extracellular vesicles from midbrain tissue of Parkinson’s disease

“…Previous studies have shown that miR-103/107 forms a negative feedback loop with HMGA1 to regulate MPP + /MPTP-induced autophagy impairment and neural cell death (Li et al, 2020).…”

Age-related changes in plasma extracellular vesicles influence neuroinflammation in the brain and neurological outcome after traumatic spinal cord injury

“…8g). Among these miRs, several (miR-93-5p, miR-107, and miR-486-5p) were reported to regulate apoptosis and cellular autophagy [26,28] and some (miR-24-3p, miR-132-3p, and miR-20a-5p) were reported to regulate inflammation response [14,43]. Collectively, these data show that EVs miRs contents are exacerbated with age and SCI, which are associated with neuroinflammation and disrupted autophagy-lysosome pathways-consistent with our NanoString results and indicating age-related dysregulation in these pathways after injury.…”