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

Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein–induced neuropathology. In mice expressing a human α-synucleinopathy–associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein–induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.

Growing evidence suggests that fine particulate matter (PM _2.5 ) likely increases the risks of dementia, yet little is known about the relative contributions of different constituents. Here, we conducted a nationwide population-based cohort study (2000 to 2017) by integrating the Medicare Chronic Conditions Warehouse database and two independently sourced datasets of high-resolution PM _2.5 major chemical composition, including black carbon (BC), organic matter (OM), nitrate (NO ₃ ⁻ ), sulfate (SO ₄ ²⁻ ), ammonium (NH ₄ ⁺ ), and soil dust (DUST). To investigate the impact of long-term exposure to PM _2.5 constituents on incident all-cause dementia and Alzheimer’s disease (AD), hazard ratios for dementia and AD were estimated using Cox proportional hazards models, and penalized splines were used to evaluate potential nonlinear concentration–response (C-R) relationships. Results using two exposure datasets consistently indicated higher rates of incident dementia and AD for an increased exposure to PM _2.5 and its major constituents. An interquartile range increase in PM _2.5 mass was associated with a 6 to 7% increase in dementia incidence and a 9% increase in AD incidence. For different PM _2.5 constituents, associations remained significant for BC, OM, SO ₄ ²⁻ , and NH ₄ ⁺ for both end points (even after adjustments of other constituents), among which BC and SO ₄ ²⁻ showed the strongest associations. All constituents had largely linear C-R relationships in the low exposure range, but most tailed off at higher exposure concentrations. Our findings suggest that long-term exposure to PM _2.5 is significantly associated with higher rates of incident dementia and AD and that SO ₄ ²⁻ , BC, and OM related to traffic and fossil fuel combustion might drive the observed associations.

Significance: Receptor-mediated cell-to-cell transmission of pathological α-synuclein (α-syn) plays an important role in the progression of Parkinson’s disease (PD). We show that α-syn uses its acidic C terminus to bind an alkaline patch on the receptors. The formation of amyloid fibrils dramatically enhances the binding by condensing α-syn molecules and better exposing the C terminus. Moreover, S129 phosphorylation, a hallmark modification of α-syn accumulation in Lewy bodies, further strengthens the electrostatic interactions between α-syn and the receptors, which accelerates the PD-like pathology in mice. This work illuminates mechanistic understanding on the spread of pathological proteins and provides structural information for the therapeutic targeting of pathological α-syn spread in PD progression.

The uptake and spread of a-synuclein pathology in the brain are governed by neuronal phenotype and connectomics.