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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.
Micronutrients for the Prevention and Improvement of the Standard Therapy for Parkinson’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
The degeneration of DA neurons of the substantia nigra is a characteristic feature of PD. Surviving neurons contains Lewy bodies, a pathological hallmark of PD. The Lewy bodies are present in other area of the brain, particularly brain stems area like the locus coeruleus that sends out processes throughout the brain. Thus, PD is not just a disease of substantia nigra DA neurons alone. The incidence of Lewy bodies in 139 autopsied brain samples of elderly individuals with normal cognitive function and without any type of movement disorders was evaluated. The results showed that about 23% of the samples contained Lewy bodies in various regions of the brains. The most common regions involved were medulla (26%), amygdale (24%), pons (20%), and midbrain (20%).25 Lewy bodies contain predominantly neurofilaments that are important components of the neuronal cytoskeleton and ubiquitin that degrades abnormal proteins. Lewy bodies also contain high levels of alpha-synuclein. The presence of another protein FOXO3 (a transcriptional activator that can trigger neuronal death upon oxidative stress) was demonstrated in Lewy bodies in the autopsied brain samples of PD as well as in the Lewy body dementia.26 Lewy bodies are considered consequences of neuronal damage. They can be transferred from one neuron to another by endocytosis. This was demonstrated by the fact that Lewy bodies were present in the neurons grafted in patients with PD and in a transgenic animal model of PD.27
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
Other anti-alpha-synuclein therapies include the use of oral UCB0599, which inhibits misfolding of alpha-synuclein. In a Phase 1/1B study, this small molecule has been found to have an acceptable safety/tolerability profile [125]. A phase 2 study in early-stage PD is currently underway (NCT04658186). The association of renin-angiotensin system (RAS) with neurodegeneration in PD has gained attention in recent times. There is evidence suggesting that activation of RAS may trigger neurodegeneration in PD via pro-oxidative and/or proinflammatory effects [126,127]. This has generated interest in utilizing angiotensin receptor blockers as a neuroprotective strategy. In fact, several retrospective cohort studies have reported an association of angiotensin receptor blocker use with a lower risk of incident PD [128–130]. Clinical trials are needed to further explore these associations.
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.
Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies
Published in mAbs, 2021
Lone Fjord-Larsen, Annemette Thougaard, Karen Malene Wegener, Joan Christiansen, Frank Larsen, Lise Maj Schrøder-Hansen, Marianne Kaarde, Dorte Kornerup Ditlevsen
As an IgG1 isotype, LuAF82422 has the potential to exert immunomodulatory functions through Fc-receptor interactions and complement activation. Consequently, an IgG1 antibody can eliminate cells with its target present on the cell surface, either by inducing antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity.43 Alpha-synuclein is expressed in platelets, erythrocytes, and leucocytes.22–26 In tissues, the target expression study confirmed that alpha-synuclein is primarily expressed in the brain and peripheral nerves in humans, cynomolgus monkeys and rats. Staining was also seen in some non-nervous tissues (pituitary, adrenal medulla, spleen, lymph node, bone marrow and skin) and considered to represent alpha-synuclein expression based on previous reports,35–37 though staining was not necessarily seen in all species or with both antisera used. The tissue cross reactivity study showed binding of LuAF82422 to brain and peripheral nerves only, and the immunotoxicity assessment was therefore focused on blood cells and neurons.