PAR promotes α-synuclein toxicity: How pathologic α-synuclein (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see the Perspective by Brundin and Wyse). They found that pathologic α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) and inhibition of PARP or knockout of PARP-1 protected mice from pathology. The generation of PAR by α-syn PFF–induced PARP-1 activation converted α-syn PFF to a strain that was 25-fold more toxic, termed PAR–α-syn PFF. An increase of PAR in the cerebrospinal fluid and evidence of PARP activation in the substantia nigra of PD patients indicates that PARP activation contributes to the pathogenesis of PD through parthanatos and conversion of α-syn to a more toxic strain. Science , this issue p. eaat8407 ; see also p. 521

Stroke is a leading cause of death and disability. The pathophysiological mechanisms associated with stroke are very complex and not fully understood. Lysosomal function has a vital physiological function in the maintenance of cellular homeostasis. In neurons, CTSD (cathepsin D) is an essential protease involved in the regulation of proteolytic activity of the lysosomes. Loss of CTSD leads to lysosomal dysfunction and accumulation of different cellular proteins implicated in neurodegenerative diseases. In cerebral ischemia, the role of CTSD and lysosomal function is not clearly defined. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons and the middle cerebral artery occlusion (MCAO) model of stroke to assess the role of CTSD in stroke pathophysiology. Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function. We found that shRNA-mediated knockdown of CTSD in neurons is sufficient to cause lysosomal dysfunction. CTSD knockdown further aggravates lysosomal dysfunction and cell death in OGD-exposed neurons. Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity in neurons and, thus, renders resistance to OGD-mediated defects in lysosomal function and cell death. This study indicates that CTSD-dependent lysosomal function is critical for maintaining neuronal survival in cerebral ischemia; thus, strategies focused on maintaining CTSD function in neurons are potentially novel therapeutic approaches to prevent neuronal death in stroke. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; FTD: frontotemporal dementia, HD: Huntington disease; LAMP1: lysosomal associated membrane protein 1; LSD: lysosomal storage disease; MCAO: middle cerebral artery occlusion; OGD: oxygen glucose deprivation; OGR: oxygen glucose resupply; PD: Parkinson disease; SQSMT1: sequestosome 1; TCA: trichloroacetic acid; TTC: triphenyl tetrazolium chloride.

Sirtuin 3 (SIRT3) is an NAD+ dependent deacetylase that resides primarily in mitochondria and functions to maintain mitochondrial homeostasis under stress. SIRT3 expression has been observed to change under a number of different stresses in multiple tissues and model systems. Inconsistencies in the literature with regards to how and when SIRT3 protein levels change indicates that the mechanism of SIRT3 regulation is multi-faceted. Alterations in SIRT3 have been observed in experimental models of cellular stress, however, the effect these changes have on mitochondrial health remain unknown. Neurons are highly dependent on proper mitochondrial function for their survival. SIRT3 dynamics and function have been studied using models of genotoxic, metabolic, and oxidative stresses, although it remains unclear how SIRT3 is being regulated under these conditions. A closer look into SIRT3 regulation under stress conditions in various model systems will help incorporate the many SIRT3 regulatory mechanisms at play in disease states. In this review, we describe the observations that have been made about SIRT3 protein modulation under basic stress conditions. We then point out consistencies and contradictions in these observations and what they mean. Lastly, we present the observations made in the complicated neuronal stress of stroke. We hope that this review will help consolidate the ambiguous SIRT3 literature and provide a framework for investigation of SIRT3 regulation during stress response.

Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.

Sulfotransferase 4A1 (SULT4A1), a member of cytosolic sulfotransferases (SULT), is exclusively expressed in neurons with no known function. Severe phenotype and early postnatal death in SULT4A1 knockout mice revealed that SULT4A1 is an essential neuronal protein. Localization of SULT4A1 in different cytosolic compartments, including mitochondria, suggests multiple roles for this protein. We observed that knockdown of SULT4A1 results in the accumulation of reactive oxygen species in primary cortical neurons, suggesting a potential role of SULT4A1 in regulating redox homeostasis. Expression of SULT4A1 in the human neuroblastoma SH-SY5Y cells revealed a defused but nonuniform staining pattern in the cytoplasm, with increased density around mitochondria. Subcellular fractionation of SULT4A1 expressing SH-SY5Y cells confirms the presence of SULT4A1 in mitochondrial fractions. SULT4A1 expressing cells display significant protection against H₂O₂-mediated defects in mitochondrial function and loss of mitochondrial membrane potential. Expression of SULT4A1 in SH-SY5Y cells also protects against H₂O₂-induced cell death. These data indicate that SULT4A1 protects mitochondria against oxidative damage and may serve as a potential pharmacological target in neural diseases involving mitochondrial dysfunction and oxidative stress. SIGNIFICANCE STATEMENT Studies on SULT4A1 knockout mice suggest that SULT4A1 plays a vital role in neuronal function and survival via yet undefined mechanisms. Our data demonstrate that depletion of SULT4A1 induces oxidative stress in neurons and expression of SULT4A1 in SH-SY5Y cells protects against oxidative-stress-induced mitochondrial dysfunction and cell death. These results suggest that SULT4A1 may have a crucial protective function against mitochondrial dysfunction and oxidative stress, and may serve a potential therapeutic target in different neurological diseases involving mitochondrial dysfunction and oxidative stress.