alpha-synuclein and Cardiovascular-Diseases

Parkinson's disease (PD) is the second-most-common neurodegenerative disease characterized by motor and non-motor dysfunctions, which currently affects about 10 million people worldwide. Gradual death and progressive loss of dopaminergic neurons in the pars compacta region of substantia nigra result in striatal dopamine deficiency in PD. Specific mutation with further aggregation of α-synuclein in the intraneuronal inclusion bodies is considered the neuropathological hallmark of this disease. PD is often associated with various organelle dysfunctions inside a dopaminergic neuron, including mitochondrial damage, proteasomal impairment, and production of reactive oxygen species, thus causing subsequent neuronal death. Apart from several genetic and non-genetic risk factors, emerging research establishes an association between cardiovascular diseases, including coronary heart disease, myocardial infarction, congestive heart failure, and ischemic stroke with PD. The majority of these cardiovascular diseases have an origin from atherosclerosis, where endothelial dysfunction following thrombus formation is significantly regulated by blood platelet. This non-nucleated cell fragment expresses not only neuron-specific molecules and receptors but also several PD-specific biomarkers such as α-synuclein, parkin, PTEN-induced kinase-1, tyrosine hydroxylase, dopamine transporter, thus making platelet a suitable peripheral model for PD. Besides its similarity with a dopaminergic neuron, platelet structural alterations, as well as functional abnormalities, are also evident in PD. However, the molecular mechanism behind platelet dysfunction is still elusive and quite controversial. This state-of-the-art review describes the detailed mechanism of platelet impairment in PD, addressing the novel platelet-associated therapeutic drug candidates for plausible PD management.

Topics: alpha-Synuclein; Blood Platelets; Cardiovascular Diseases; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; Precision Medicine; Substantia Nigra

In recent years progress has been made in the detection and evaluation of nonmotor symptoms in Parkinson's disease. The pathophysiology is better understood and new treatment is available, which will be discussed in this review.. The most intriguing recent finding is the fact that Parkinson's disease may be a spreading disease. From the environment a toxin, bacteria, or virus may start in genetically susceptible patients a cascade of α-synuclein aggregation which reaches via the olfactory and the enteric system of the gut the brain where further spreading causes symptoms, such as sleep disturbances, motor impairment, and neuropsychiatric symptoms. New treatment should address the abnormal α-synuclein folding. If this would be achieved premotor signs, such as hyposmia, rapid eye movement-sleep behavior disorder, constipation, or depression may be a kind of biomarkers which allow together with other diagnostic tools, such as parenchymal sonography, iodobenzamide-scintigraphy and dopamine transporter scans the prediction whether somebody might be under way to develop the full-blown Parkinson's disease syndrome.. Parkinson's disease seems to be a spreading disease which causes not only a dopaminergic deficit as major cause for the movement disorder but also impairs function of many other brain centers which leads to a multitransmitter malfunction.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Cardiovascular Diseases; Dyskinesias; Early Diagnosis; Erectile Dysfunction; Fatigue; Gastrointestinal Diseases; Humans; Male; Mental Disorders; Movement Disorders; Olfaction Disorders; Pain; Parkinson Disease; Sleep Wake Disorders; Urologic Diseases

Cardiovascular autonomic dysfunction is a common non-motor symptom associated with synucleinopathies such as Parkinson's disease (PD). Several recent clinical studies indicate that cardiovascular autonomic impairments including orthostatic hypotension and sympathetic denervation may precede the development of the cardinal motor symptoms in PD, making cardiovascular dysfunction an attractive target for the development of biomarkers for early detection and potential neuroprotective strategies for PD. However, the pathologic mechanisms underlying cardiovascular dysfunction as well as many of the non-motor symptoms in PD remain unknown. This is likely due, in part, to an initial under-appreciation of PD as a systemic disorder as well as limited research in cardiovascular dysfunction in animal models of PD. Here, we highlight studies that have investigated cardiovascular dysfunction in rodent models of PD and the potential usefulness of genetic mouse models of PD for this endeavor.

Topics: alpha-Synuclein; Animals; Autonomic Nervous System Diseases; Blood Pressure; Cardiovascular Diseases; Disease Models, Animal; Heart Rate; Humans; Parkinson Disease

Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).. The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.. 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.. Hyperphosphorylated τ (HPτ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α-synuclein (αS) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.. In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, αS, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC.

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus; Female; Humans; Lewy Bodies; Male; Phosphorylation; tau Proteins; Tauopathies