The Braak hypothesis in prion disease with a focus on Creutzfeldt-Jakob disease.

This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt-Jakob disease (CJD). In CJD, we can speculate on the pathological onset region to some degree in reference to the clinical symptoms and magnetic resonance imaging findings. Although relating the Braak hypothesis to prion disease is not straightforward, the following could be proposed based on experimental and previously reported case observations. Pathogenic abnormal prion protein (PrP) deposition in the central nervous system (CNS) probably begins several months or years before clinical symptom onset, signifying the potentiality of a preclinical stage, similar to α-synuclein deposition in Parkinson's disease (PD) and amyloid-ß/tau deposition in Alzheimer's disease (AD). Unlike in PD and AD, the initial clinical symptoms of CJD vary by case, and thus the onset lesions must also be various and multiple in the CNS. Based on the pathological findings, particularly of PrP deposition extensively observed in the CNS gray matter of autopsy cases, it could be speculated that in the early disease stage, including the preclinical stage, abnormal PrP spreads from the onset region without directionality or hierarchy. Because each CNS region shows either vulnerability to or resistance against PrP deposition and pathological progression in prion disease, the lesion distribution shows system degeneration. Although pathologically combined cases of type 1 and type 2 PrP patterns are often recognized, type 1 and type 2 PrP patterns must never shift toward each other during the disease course; in other words, the original type of PrP deposition in each region presumably remains unchanged in each case. According to the several observations and corresponding speculations, there are at least partial similarities between prion disease and protein propagation, as explained by the Braak hypothesis, in terms of pathological lesion progression, but several noted contradictions preclude the hypothesis from comprehensively accounting for prion disease.

Spreading of alpha-synuclein - relevant or epiphenomenon?

The intracellular accumulation of misfolded alpha-synuclein pathology, termed Lewy pathology, throughout the brain is a phenomenon central to Parkinson's disease pathogenesis. In recent years it has become apparent that Lewy pathology can spread from neuron-to-neuron and between interconnected brain regions. Understanding the phenomenon of Lewy pathology propagation holds great promise in its explanatory power to determine the etiology of Parkinson's disease and related synucleinopathies. However, it remains to be seen if the spread of Lewy pathology is critical for driving this disease. Here we discuss the spreading of Lewy pathology while highlighting some important concepts and experimental observations. We conclude that further studies are required to determine if, and how, the spreading behavior of Lewy pathology is involved in Parkinson's disease. "This article is part of the Special Issue Synuclein".

An order in Lewy body disorders: Retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease.

Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected early, which is clinically detectable as reduced myocardial uptake of meta-iodobenzylguanidine in PD/DLB. Because each Lewy-prone system develops LBs independently, their isolated presentation as "focal LB disease" or their whatever combinations as "multifocal LB disease" are a more plausible framework to explain clinicopathological diversities of LB disorders. Clinical criteria are now being revised to integrate these clinicopathological disorders of PD/DLB. To gain closer access to the reality of the human brain, it is necessary to facilitate more interactions between clinicopathological and experimental fields so that both are mutually critical and complementary for improved diagnosis and treatment.

Intercellular transmission of alpha-synuclein.

An emerging theme in Parkinson's disease (PD) is the propagation of α-synuclein pathology as the disease progresses. Research involving the injection of preformed α-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of α-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for α-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of α-synuclein in extracellular vesicles.

Cognitive heterogeneity in Parkinson's disease: A mechanistic view.

Cognitive impairment occurs in most individuals with Parkinson's disease (PD), exacting a high toll on patients, their caregivers, and the healthcare system. In this review, we begin by summarizing the current clinical landscape surrounding cognition in PD. We then discuss how cognitive impairment and dementia may develop in PD based on the spread of the pathological protein alpha-synuclein (aSyn) from neurons in brainstem regions to those in the cortical regions of the brain responsible for higher cognitive functions, as first proposed in the Braak hypothesis. We appraise the Braak hypothesis from molecular (conformations of aSyn), cell biological (cell-to-cell spread of pathological aSyn), and organ-level (region-to-region spread of aSyn pathology at the whole brain level) viewpoints. Finally, we argue that individual host factors may be the most poorly understood aspect of this pathological process, accounting for substantial heterogeneity in the pattern and pace of cognitive decline in PD.

α-Synuclein-mediated neurodegeneration in Dementia with Lewy bodies: the pathobiology of a paradox.

Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of α-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the α-synuclein protein inexorably undergoes extensive conformational metamorphoses and culminate in the form of fibrillar polymorphs, instigating calamitous damage to the brain's neuropsychological networks. This epiphenomenon is nebulous, however, by lingering uncertainty over the quasi "pathogenic" behavior of α-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic "α-synuclein" paradigm that is able to untangle the enigma enshrouding the clinicopathological spectrum of DLB has failed to emanate. In this article, we review conceptual frameworks of α-synuclein dependent cell-autonomous and non-autonomous mechanisms that are likely to facilitate the transneuronal spread of degeneration through the neuraxis. In particular, we describe how the progressive demise of susceptible neurons may evolve from cellular derangements perpetrated by α-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate α-synuclein-mediated neurodegeneration in the DLB brain.

Early-Onset Parkinson's Disease With Multiple Positive Intraoperative Spinal Tissue Cultures for Cutibacterium acnes.

An estimated 95-97% of Parkinson's disease (PD) cases are idiopathic, emphasizing the absence of a clear etiologic linkage for this debilitating, neurodegenerative, and progressive motor disease. Increasing evidence suggests a peripheral disease origin and the gradual transition of a pathological process along the gut-brain axis and olfactory routes into the brain. This disease pattern is reminiscent of an infectious process and suggests the presence of one or multiple infectious agents, such as bacteria, viruses, fungi, or prion-like proteins. This unusual paradigm, known as Braak's hypothesis, was first described by the scientist who developed the staging standard for cellular PD pathology and. Here, we describe a case where the small, anaerobic, Gram-positive Cutibacterium acnes was recurrently isolated from intraoperative spinal tissues in a patient with early-onset PD. C. acnes is also the bacterium that we previously isolated from cadaveric PD brain tissue. Both observations are consistent with Braak's hypothesis underscoring the importance of homeostasis and maintained immune-competence for healthy aging of the body and mind.

Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms' including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein.

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread.

Modeling Parkinson's Disease With the Alpha-Synuclein Protein.

Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of α-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of α-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes α-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the α-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of α-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on α-Syn have been generated. In this review, we summarize the main features of the α-Syn pre-formed fibrils (PFFs) model and recombinant adeno-associated virus vector (rAAV) mediated α-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. SIGNIFICANCE: Here, we show that injection of α-Syn PFFs and overexpression of α-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, α-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the α-Syn pathology. In contrast, rAAV-mediated α-Syn overexpression in the brain limits the α-Syn aggregates within the transduced neurons. Second, phosphorylated α-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas α-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated α-Syn reminiscent of Lewy bodies and Lewy neurites.

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. In-vivo human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients (N = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients (N = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects (N = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are "higher" in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease.

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).

Exploring Braak's Hypothesis of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder for which there is no cure. Most patients suffer from sporadic PD, which is likely caused by a combination of genetic and environmental factors. Braak's hypothesis states that sporadic PD is caused by a pathogen that enters the body via the nasal cavity, and subsequently is swallowed and reaches the gut, initiating Lewy pathology (LP) in the nose and the digestive tract. A staging system describing the spread of LP from the peripheral to the central nervous system was also postulated by the same research group. There has been criticism to Braak's hypothesis, in part because not all patients follow the proposed staging system. Here, we review literature that either supports or criticizes Braak's hypothesis, focused on the enteric route, digestive problems in patients, the spread of LP on a tissue and a cellular level, and the toxicity of the protein αSynuclein (αSyn), which is the major constituent of LP. We conclude that Braak's hypothesis is supported by in vitro, in vivo, and clinical evidence. However, we also conclude that the staging system of Braak only describes a specific subset of patients with young onset and long duration of the disease.