Connecting the dots: Neuronal senescence, stress granules, and neurodegeneration

Abstract

Cellular senescence increases with aging. While senescence is associated with an exit of the cell cycle, there is ample evidence that post-mitotic cells including neurons can undergo senescence as the brain ages, and that senescence likely contributes significantly to the progression of neurodegenerative diseases (ND) such as Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Stress granules (SGs) are stress-induced cytoplasmic biomolecular condensates of RNA and proteins, which have been linked to the development of AD and ALS. The SG seeding hypothesis of NDs proposes that chronic stress in aging neurons results in static SGs that progress into pathological aggregates Alterations in SG dynamics have also been linked to senescence, though studies that link SGs and senescence in the context of NDs and the aging brain have not yet been performed. In this Review, we summarize the literature on senescence, and explore the contribution of senescence to the aging brain. We describe senescence phenotypes in aging neurons and glia, and their links to neuroinflammation and the development of AD and ALS. We further examine the relationships of SGs to senescence and to ND. We propose a new hypothesis that neuronal senescence may contribute to the mechanism of SG seeding in ND by altering SG dynamics in aged cells, thereby providing additional aggregation opportunities within aged neurons.

Keywords: Alzheimer’s Disease; Amyotrophic Lateral Sclerosis (ALS); Neurodegeneration; Neuroinflammation; Neuronal aging; Senescence; Senescence-associated secretory phenotype (SASP); Stress granules.

Figure 1.. Aging connects neuroinflammation, senescence, SGs formation, and NDs.

Aging is a central factor that connects neuroinflammation, senescence, SGs, and ND. Shortened telomeres, oncogenes, DNA damage accumulation, and other factors lead to senescence during aging. Both neuroinflammation and aging are major risk factors of neurodegenerative diseases. Aging promotes SGs formation by dysfunctional mitochondria, presence of chronic stress, and decline in protein homeostasis. SGs promote NDs by seeding hypothesis which causes aggregation of pathological proteins such as TDP-43 and tau. Accumulation of senescent cells during aging promotes neuroinflammation at the early stage by secreting SASP, and SASP further aggravates senescence. The senescent cells form smaller but more numerous SGs which implies impairments in the SGs formation pathway. See text for more information.

Figure 2.. Mechanisms of senescence.

Senescence can be induced by DNA damage, telomere erosion, and oncogene activation. DNA damage, telomere erosion, and activation of oncogenes MYC and RAS lead to activation of DDR. Activation of PI3K and MYC also induces ARF transcription which leads to senescence via the p53 pathway. Activated ATM/ATR kinase results in p53 induction. Successful DNA damage repair allows cell cycle progression. Failure in DNA damage repair leads to either apoptosis or senescence by p53-induced p21 transcription. P21 inhibits the cyclinE-CDK2 complex and causes RB to be maintained in a hypophosphorylated state. Activation of RAS also mediates P16INK4A induction which inhibits cyclin D-CDK4/CDK6 complex and RB hyperphosphorylation. Hypophosphorylated RB binds and sequesters transcription factor E2F and causes cell cycle arrest in the G1 phase. This early step in senescence results in senescence-associated β-galactosidase activity. Later events include morphological effects, SAFH, and SASP. Increasing SASP in chronic senescence can trigger senescence in neighboring cells. The exact mechanism of how post-mitotic neurons undergo senescence is unknown, though increased SASP, neuroinflammation, and declining cell function attributable to senescence are believed to play a role in neurodegeneration. Adapted from Saez-Atienzar and Masliah, 2020.

Figure 3.. Hypothetical model of senescence, SGs, and NDs.

Post-mitotic neurons accumulate senescent phenotypes during aging. Among these phenotypes, senescent neurons may produce smaller but more abundant SGs, which may provide additional opportunities for aggregate seeding and thereby further exacerbate NDs. See text for additional details.