Age-Related Midbrain Inflammation and Senescence in Parkinson’s Disease

Abstract

Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive. In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic (DA) neurons in PD.

SARS-CoV-2 infection causes dopaminergic neuron senescence

“…Since DA neurons are one of the major cell types degenerated in PD, and DA neuron senescence has been shown to be associated with PD, 20 we next monitored how PD-iPSC-derived DA neurons responded to SARS-CoV-2 infection. SNCA , the first gene associated with familial PD, encodes the protein α-synuclein (α-Syn).…”

Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases

“…Senescent EC accumulation leads to increased SASP which further stimulate neuroinflammation. In PD, BBB becomes senescent causing impairment of BBB integrity ( Russo and Riessland, 2022 ). Senescent astrocytes and SASP factors are elevated in Parkinsonian substantia nigra pars compacta.…”

“…To disentangle the relationship between inflammation and senescent cells, it is critical to understand the potential origins of diverse midbrain cell types and how paracrine spreading of senescent cells amongst them may lead to observed local immune responses. The immune cell-mediated death of dopaminergic (DA) neurons in the midbrain of PD patients is the pro-inflammatory substance released by senescent cells ( Russo and Riessland, 2022 ).…”

Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics

“…For example, the neuroscience field has identified senescent cells in multiple CNS diseases and disorders, and emerging data highlight their critical importance in driving disease phenotypes. Specifically, beyond amyloid and tau, defective autophagy ( 114 , 115 ); insulin resistance/obesity ( 110 , 116 ); traumatic brain injury (TBI) ( 117 ); depression ( 118 ); alcohol use disorder ( 119 ), Parkinson’s disease ( 120 ) and pain ( 121 ) all reportedly increase CNS senescent cell burden. Given the epidemiology linking each of these independently to increased AD risk, targeting senescent cells in early disease stages (preclinical and/or prodromal) may hold promise to prevent chronic neurodegeneration and dementia.…”