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Special Considerations in Gaze
Published in Vivek Lal, A Clinical Approach to Neuro-Ophthalmic Disorders, 2023
Mohamed Elkasaby, Aasef G. Shaikh
Dementia with Lewy bodies (DLB), characterized by the presence of eosinophilic intracytoplasmic inclusions called Lewy bodies, which consist of aggregations of alpha-synuclein within neurons. The key clinical features are parkinsonism, cognitive impairment, visual hallucinations, autonomic dysfunction, a fluctuating mental state and REM sleep behavior disorder [73–75]. Hypometria as well as slowing of saccades are reported in DLB [76]. The latency of visually guided saccade initiation is increased and there are more directional errors during antisaccade tasks in patients with DLB [76, 77].
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The incidence of DLB in monozygotic twins is discordant, indicating that environmental and/or epigenetic factors play a role in disease pathogenesis. However, risk factors for DLB have not been clearly identified to date. Most cases are sporadic and late onset, though familial cases have been reported. The heritable component of DLB has been estimated to be approximately 36% based on one genome-wide association study.29 Mutations in genes linked to other neurodegenerative disease have also been implicated in DLB, including: SNCA: encoding alpha-synuclein protein.ApoE: encoding apolipoprotein E.APP: encoding amyloid precursor protein.PSEN-1/PSEN-2: encoding presenilin.MAPT: encoding microtubule-associated protein tau.GBA: encoding glucocerebrosidase.CNTN1: encoding contactin 1 (J).
Modelling human neurodegeneration using induced pluripotent stem cells
Published in Christine Hauskeller, Arne Manzeschke, Anja Pichl, The Matrix of Stem Cell Research, 2019
Iryna Prots, Beate Winner, Jürgen Winkler
Current belief is that better understanding the sequence of events that leads to the loss of dopaminergic neurons could provide us with the necessary knowledge to develop new successful treatments of PD. At present, several relevant pathological characteristics are known. The main neuropathological hallmark of PD is a formation of aggregates (clumps) of a protein alpha-synuclein, which are also called Lewy Bodies or Lewy Neurites, depending on their location in the neuronal cell: cell body or axon, respectively (Spillantini et al., 1997). The appearance of alpha-synuclein aggregates in neurons in different areas of the brain at different disease stages correlates with respective symptoms and with the time of their manifestation. Additionally, the loss of axons and dendrites very early during the course of the disease results in reduced or lost neuronal connectivity between different brain regions (Kalia and Lang, 2015). Finally, inflammatory processes due to the activation of brain immune cells, such as microglia, accompany and enhance neuronal degeneration thereby modulating disease progression. Each of these processes leads to neuronal death, but how they collude to result in the above-described PD symptoms needs to be understood.
How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease?
Published in Expert Review of Neurotherapeutics, 2023
Abhishek Lenka, Joseph Jankovic
One of the prime topics in the field of research on preventive or neuroprotective treatment of neurodegenerative diseases is the controversy whether aggregated proteins such as alpha-synuclein in PD or amyloid/tau in AD are pathogenic or mere byproducts of other pathogenic mechanisms (‘villain’ or ‘victim’). Numerous trials have been based on the widely assumed theory that the misfolded naturally occurring proteins become toxic to the brain [115]. This theory, however, has been increasingly challenged as some argue that rather than accumulation of toxic aggregated alpha-synuclein (gain of function) the primary pathogenic mechanism in PD is depletion of normal healthy soluble alpha-synuclein (loss of function) which is crucial for several physiologic functions in the brain [116–118]. However, it is not clear how the alternative hypothesis of ‘proteinopenia’ can be incorporated in designing future potential DMTs [118]. Since in most neurodegenerative diseases multiple mechanisms and rogue proteins (alpha-synuclein, tau, amyloid, etc) likely play an important role future DMT trial should seek multiple target engagements [118–120].
Role of exosomes and its emerging therapeutic applications in the pathophysiology of non-infectious diseases
Published in Biomarkers, 2022
Gauresh G. Shivji, Rajib Dhar, Arikketh Devi
Parkinson’s disease (PD) results in reduced levels of dopamine in the brain due to the damage to the nerve cells of substantia nigra. A protein called alpha-synuclein (α-syn) aggregates forming Lewy bodies (LBs) and results in neuronal death (Tofaris 2017). Exosomes from PD patients are said to contain oligomeric α-syn protein in them. This form of α-syn is more toxic and is easily taken up by the neuronal cells when compared to the free α-syn (Danzer et al. 2012). Exosomes act as carriers of α-syn which interacts with the nearby cells and induces apoptosis (Sung et al. 2001, Wu et al.2017). α-syn levels in blood or CSF cannot act as biomarkers as there is no specified levels of this protein for an individual (Ohmichi et al. 2019). In addition, the levels of apolipoprotein A1 in the plasma-derived exosomes were less in the earlier stages of the PD and more in the later stages, and thus it can be used as a biomarker to monitor the disease progression. Similarly, other proteins derived from these exosomes can be used to diagnose PD such as clusterin, complement C1r subcomponent and the fibrinogen gamma chain (Kitamura et al. 2018). Also, insulin signalling markers from brain-derived exosomes can help identifying PD pathogenesis in early stages (Kitamura et al. 2018). Thus the exosomes derived from brain cells are the best easily available biomarkers for the diagnosis of PD patients. .
Is PROTAC technology really a game changer for central nervous system drug discovery?
Published in Expert Opinion on Drug Discovery, 2021
Kayla Farrell, Timothy J. Jarome
Parkinson’s disease is a neurodegenerative disorder that affects 1–3% of the population over 80 years of age. The main characteristic of Parkinson’s disease is accumulation of alpha-synuclein protein (α-syn), which leads to the formation of Lewy-bodies [35]. A recent investigation demonstrated the ability of PROTACs technology to target α-syn [36]. This study combined an α-syn protein binding domain, a cell-penetrating domain, and a proteasome-targeting motif to generate a cell-permeable PROTAC, which was able to target α-syn for degradation by the proteasome in a time- and dose-dependent manner in primary neurons and neuroblastoma cells. The reduction in α-syn lead to decreased mitochondrial dysfunction and cell toxicity, indicating the potential of the PROTAC as a potential strategy to treat Parkinson’s disease. Importantly, though these results are exciting, this in vitro study will need further validation to determine if this method has potential clinical applications.