Synucleinopathies, including Parkinson’s disease (PD), Lewy body dementia (LBD), Alzheimer’s disease with amygdala restricted Lewy bodies (AD/ALB), and multiple system atrophy (MSA) comprise a spectrum of neurodegenerative disorders characterized by the presence of distinct pathological α-synuclein (αSyn) inclusions. Experimental and pathological studies support the notion that αSyn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of αSyn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of αSyn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote αSyn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in αSyn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the αSyn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the substantia nigra and amygdala were positive for αSyn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain αSyn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD/ALB, these modifications were only weakly or not detected in amygdala αSyn inclusions. αSyn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved αSyn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the αSyn x-122 neo-epitope but did not display any reactivity for αSyn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal αSyn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases.

Beginning in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a novel pathogen that causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 has infected more than 111 million people worldwide and caused over 2.47 million deaths. Individuals infected with SARS-CoV-2 show symptoms of fever, cough, dyspnea, and fatigue with severe cases that can develop into pneumonia, myocarditis, acute respiratory distress syndrome, hypercoagulability, and even multi-organ failure. Current clinical management consists largely of supportive care as commonly administered treatments, including convalescent plasma, remdesivir, and high-dose glucocorticoids. These have demonstrated modest benefits in a small subset of hospitalized patients, with only dexamethasone showing demonstrable efficacy in reducing mortality and length of hospitalization. At this time, no SARS-CoV-2-specific antiviral drugs are available, although several vaccines have been approved for use in recent months. In this review, we will evaluate the efficacy of preclinical and clinical drugs that precisely target three different, essential steps of the SARS-CoV-2 replication cycle: the spike protein during entry, main protease (MPro) during proteolytic activation, and RNA-dependent RNA polymerase (RdRp) during transcription. We will assess the advantages and limitations of drugs that precisely target evolutionarily well-conserved domains, which are less likely to mutate, and therefore less likely to escape the effects of these drugs. We propose that a multi-drug cocktail targeting precise proteins, critical to the viral replication cycle, such as spike protein, MPro, and RdRp, will be the most effective strategy of inhibiting SARS-CoV-2 replication and limiting its spread in the general population.

Multiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA.

Background The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid β (Aβ) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration. Methods To assess the interplay between α-synuclein and Aβ on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later. Results Immunohistochemical analysis of M20/L85 mice revealed that pre-existing Aβ plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aβ; whereas the level of Aβ deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS. Conclusions These studies reveal novel and unexpected interplays between α-synuclein pathology, Aβ and neuroinflammation in mice that recapitulate the pathology of Alzheimer’s disease and Lewy body dementia.

Degeneration of locus coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter. These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine (DA) metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.