Review
Biochemistry & Molecular Biology
Talha Siddiqui, Lokesh Kumar Bhatt
Summary: Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons and presents with motor and non-motor symptoms. The main factors contributing to neuron loss include alpha-synuclein aggregates, neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Activation of Sigma-1 receptors has shown neuroprotective and neurorestorative effects in various diseases and can modulate multiple pathophysiological features of Parkinson's disease.
NEUROCHEMICAL RESEARCH
(2023)
Article
Neurosciences
Zhihua Liu, Aijuan Yan, Jiahao Zhao, Shuyuan Yang, Lu Song, Zhenguo Liu
Summary: The study revealed the important role of p75NTR in patients with Parkinson's disease and suggested it as a new target for managing L-dopa-induced dyskinesia.
EXPERIMENTAL NEUROLOGY
(2021)
Article
Clinical Neurology
Esra Toplu Uslu, Murat Mengi, Elmas Beyazyuz, Aliye Celikkol, Yakup Albayrak
Summary: This study established an animal model of TD by administering haloperidol to rats and evaluated the efficacy of fluvoxamine in ameliorating TD symptoms. The results demonstrated that fluvoxamine treatment showed significantly improved behavioral observations and higher levels of SOD, BDNF, and NGF in the striatum compared to the haloperidol group. Additionally, the MDA levels in the hippocampus were significantly lower in the haloperidol + fluvoxamine group. These findings suggest that fluvoxamine may be a potential alternative treatment for TD.
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
(2023)
Article
Clinical Neurology
Olivier Rascol, Rossella Medori, Corine Baayen, Pedro Such, Didier Meulien
Summary: There was no evidence that foliglurax has efficacy in improving levodopa-induced motor complications in patients with Parkinson's disease.
MOVEMENT DISORDERS
(2022)
Review
Biochemistry & Molecular Biology
Kathryn Lanza, Christopher Bishop
Summary: Parkinson's Disease (PD) and long-term L-DOPA treatment induce plasticity that contributes to L-DOPA-induced dyskinesia (LID), with the dopamine D3 receptor (D3R) emerging as a promising target in LID management due to its upregulation in LID. D3R undergoes dynamic changes in both PD and LID, and recent genetic and pharmacologic tools have helped clarify its role in LID.
Article
Neurosciences
Cynthia Kwan, Imane Frouni, Stephen G. Nuara, Sebastien Belliveau, Woojin Kang, Adjia Hamadjida, Dominique Bedard, Francis Beaudry, Michel Panisset, Jim C. Gourdon, Philippe Huot
Summary: The study demonstrated that concurrent antagonising of 5-HT2A and activation of mGlu(2) receptors could provide greater anti-dyskinetic and anti-psychotic effects than either approach alone. Additionally, mGlu(2) activation may enhance the therapeutic effects of 5-HT2A blockade, potentially offering relief beyond current therapies for PD patients with dyskinesia and psychotic symptoms.
Article
Clinical Neurology
Valtteri Kaasinen, Sheng Luo, Pablo Martinez-Martin, Christopher G. G. Goetz, Glenn T. T. Stebbins
Summary: This study compared patient and clinician evaluations of levodopa-induced dyskinesia (LID) severity across multiple cultures in patients with Parkinson's disease (PD). The results showed that language and cultural differences influence the subjective perception of LID, which is important to consider in multinational clinical trials on dyskinesia assessment.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Qian-Ya Fan, Xiao-Dong Zhang, Ze-Di Hu, Shi-Shi Huang, Shi-Guo Zhu, Cai-Ping Chen, Xiong Zhang, Jian-Yong Wang
Summary: This case report presents a patient with Parkinson's disease who developed blepharospasm during the peak-dose dyskinesia period. The symptom was improved by taking amantadine. This expands the understanding of peak-dose dyskinesia in Parkinson's disease to include dystonic blepharospasm, which may respond to amantadine despite the dystonic appearance of movements.
FRONTIERS IN NEUROLOGY
(2022)
Article
Neurosciences
Piniel Alphayo Kambey, Wen Ya Liu, Jiao Wu, Chuanxi Tang, Wokuheleza Buberwa, Adonira Saro, Alphonce M. K. Nyalali, Dianshuai Gao
Summary: This study revealed the crucial role of Amphiregulin (Areg) gene in levodopa-induced dyskinesia in Parkinson's disease. Inhibition of Areg was found to alleviate dyskinetic movements and decrease the expression of related proteins. Therefore, Areg may serve as a potential target for therapy development.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Edijs Vavers, Liga Zvejniece, Maija Dambrova
Summary: In the past decade, sigma-1 receptor (Sig1R) has emerged as a promising target for the treatment of seizure disorders. Clinical trials are currently underway to test Sig1R ligands as therapies for drug-resistant seizures and other related conditions. However, the precise molecular mechanism by which Sig1R modulates seizures and the balance between excitation and inhibition pathways remain unclear.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Tung-Tai Kuo, Yuan-Hao Chen, Vicki Wang, Eagle Yi-Kung Huang, Kuo-Hsing Ma, Nigel H. H. Greig, Jin Jung, Ho- Choi, Lars Olson, Barry J. J. Hoffer, Kuan-Yin Tseng
Summary: This study evaluated the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors and neurochemistry in a progressive Parkinson's disease MitoPark mouse model. The results showed that early administration of PT320 significantly reduced the severity of L-DOPA-induced abnormal involuntary movements, particularly in excessive standing and abnormal paw movements. However, late administration of PT320 did not improve any L-DOPA-induced dyskinesia measurements. Furthermore, early treatment with PT320 increased both tonic and phasic release of dopamine in striatal slices, indicating its potential role in alleviating L-DOPA-induced dyskinesia in Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Thomas Oh, Elyas S. Daadi, Jeffrey Kim, Etienne W. Daadi, Peng-Jen Chen, Gourav Roy-Choudhury, Jonathan Bohmann, Benjamin E. Blass, Marcel M. Daadi
Summary: Parkinson's disease is a complex multisystem chronic disease for which levodopa is the main pharmacotherapy, but it often leads to levodopa-induced dyskinesia within 5 years. A new small molecule compound PD13R has been discovered to eliminate levodopa-induced dyskinesia and improve PD symptoms. Further studies are focused on developing PD13R as a treatment for PD patients with dyskinesia.
EXPERIMENTAL NEUROLOGY
(2022)
Article
Geriatrics & Gerontology
Jinyoung Youn, Mansu Kim, Suyeon Park, Ji Sun Kim, Hyunjin Park, Jin Whan Cho
Summary: This study investigates the structural changes in the basal ganglia related to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). The results demonstrate distinct shape alterations, especially in the globus pallidus interna (GPi), in the LID group compared to the non-LID group. These findings suggest the crucial role of the basal ganglia pathway in the development of LID.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Neurosciences
Bruno L. Santos-Lobato, Luiz Gustavo Gardinassi, Mariza Bortolanza, Ana Paula Ferranti Peti, Angela V. Pimentel, Lucia Helena Faccioli, Elaine A. Del-Bel, Vitor Tumas
Summary: Metabolomic analysis revealed a distinct metabolic profile associated with levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), particularly characterized by dysregulation of the glycosphingolipid metabolic pathway and bile acid biosynthesis metabolites in plasma and CSF. These findings suggest a potential link between lipid metabolism dysregulation and LID in PD.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Neurosciences
Yong Wang, Lu Yao, Shasha Gao, Gejuan Zhang, Qiongchi Zhang, Wanyuan Liu, Yingqiong Zhou, Yina Sun, Jie Feng, Jian Liu
Summary: The study found that the striatal dopamine D-5 receptor plays an important role in the pathophysiology of levodopa-induced dyskinesia in patients with Parkinson's disease, by regulating the activity of sensorimotor striatum neurons to affect the development of dyskinetic symptoms.
Article
Biochemistry & Molecular Biology
Ligia Fao, Patricia Coelho, Luis Duarte, Rita Vilaca, Michael R. Hayden, Sandra I. Mota, Ana Cristina Rego
Summary: This study demonstrates that c-Src/Fyn proteins play an important role in controlling mitochondrial function and redox regulation in Huntington's disease (HD). Restoring c-Src/Fyn levels in HD improves mitochondrial morphology and function, reducing the levels of oxidant species and cell death. These findings suggest that c-Src/Fyn could be a potential therapeutic target for HD.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Cell Biology
Shao-Ming Wang, Hsiang-En Wu, Yuko Yasui, Michal Geva, Michael Hayden, Tangui Maurice, Mauro Cozzolino, Tsung-Ping Su
Summary: Autophagy is a crucial cellular process with implications in various diseases. In this study, researchers discovered that the molecular chaperone SIGMAR1 is involved in the transport of TFEB into the nucleus by chaperoning the NP protein POM121, which is responsible for recruiting KPNB1. The disruption of this process in ALS-FTD patients with the C9orf72 subtype leads to impaired autophagy. However, overexpression of SIGMAR1 or POM121, as well as treatment with pridopidine, a SIGMAR1 agonist, can rescue these deficits, suggesting their potential therapeutic use.
Article
Clinical Neurology
Robert A. Hauser, Hadas Barkay, Amanda Wilhelm, Maria Wieman, Juha-Matti Savola, Mark Forrest Gordon
Summary: This study aimed to evaluate the minimal clinically important change in total motor AIMS score in TD patients treated with deutetrabenazine. The results showed that a reduction of 2 points in AIMS score is associated with clinically meaningful improvement in TD symptoms.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Clinical Neurology
Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Stewart A. Factor, Joohi Jimenez-Shahed, Nicholas Gross, Leslie Marinelli, Amanda Wilhelm, Jessica Alexander, Mark Forrest Gordon, Juha-Matti Savola, Karen E. Anderson
Summary: The study highlights the long-term efficacy and safety of deutetrabenazine in patients with tardive dyskinesia, showing sustained improvement in AIMS scores and no need for dose escalation over time. Deutetrabenazine was well tolerated with low rates of adverse events, indicating its potential as a beneficial long-term treatment option.
FRONTIERS IN NEUROLOGY
(2022)
Article
Astronomy & Astrophysics
Yaguang Li, Timothy R. Bedding, Simon J. Murphy, Dennis Stello, Yifan Chen, Daniel Huber, Meridith Joyce, Dion Marks, Xianfei Zhang, Shaolan Bi, Isabel L. Colman, Michael R. Hayden, Daniel R. Hey, Gang Li, Benjamin T. Montet, Sanjib Sharma, Yaqian Wu
Summary: A star expands into a red giant when all the hydrogen in its core has fused into helium. In binary systems, the envelope of the star can overflow onto its companion or be ejected into space, potentially forming a subdwarf B star. By observing thousands of helium-burning red giants, scientists have identified two classes of stars that have undergone significant mass loss, possibly due to stripping in binary interactions.
Article
Biochemistry & Molecular Biology
Carla Lopes, I. Luisa Ferreira, Carina Maranga, Margarida Beatriz, Sandra I. Mota, Jose Sereno, Joao Castelhano, Antero Abrunhosa, Francisco Oliveira, Maura De Rosa, Michael Hayden, Mario N. Laco, Cristina Januario, Miguel Castelo Branco, A. Cristina Rego
Summary: Deficits in mitochondrial function and redox deregulation occur in early stages of Huntington's disease and can progress with disease manifestation.
Article
Clinical Neurology
Samuel Frank, Claudia Testa, Mary C. Edmondson, Jody Goldstein, Elise Kayson, Blair R. Leavitt, David Oakes, Christine O'Neill, Christina Vaughan, Jacquelyn Whaley, Nicholas Gross, Mark Forrest Gordon, Juha-Matti Savola
Summary: This study evaluated the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease. The results showed that adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time and there was no unexpected worsening of chorea upon treatment cessation.
Article
Biology
Pawel Joachimiak, Adam Ciesiolka, Emilia Kozlowska, Pawel M. Switonski, Grzegorz Figura, Agata Ciolak, Grazyna Adamek, Magdalena Surdyka, Zaneta Kalinowska-Poska, Maciej Figiel, Nicholas S. S. Caron, Michael R. R. Hayden, Agnieszka Fiszer
Summary: This study used SNP variants to quantitatively determine the allele-specific expression levels in patient-derived cell lines for spinocerebellar ataxia type 3 (SCA3) and Huntington's disease (HD). They found differences in allele expression levels and developed a reliable and quantitative method using SNP-based droplet digital PCR (ddPCR) to analyze low abundant transcripts. This allele-selective approach provides insights into allele-related mechanisms and can improve understanding of polyglutamine diseases.
Article
Physiology
Fanny L. Lemarie, Shaun S. Sanders, Yen Nguyen, Dale D. O. Martin, Michael R. Hayden
Summary: Huntington's disease is a neurodegenerative disorder caused by CAG repeat expansion in the HTT gene. We found that huntingtin protein can be palmitoylated at cysteine 214, and proteolytic cleavage at aspartate 552 leads to myristoylation at glycine 553. Blocking caspase cleavage at aspartate 586 increases myristoylation of huntingtin and promotes the interaction between C-terminal and N-terminal fragments.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Neurosciences
Laura Lynn Chan, Austin Hill, Ge Lu, Jeremy Van Raamsdonk, Randy Gascoyne, Michael R. Hayden, Blair R. Leavitt
Summary: There is no significant effect of mutant or overexpression of huntingtin protein on overall survival in mouse models of cancer, which contradicts the hypothesis that mutant huntingtin expression is protective against cancer.
JOURNAL OF HUNTINGTONS DISEASE
(2022)
Article
Neurosciences
James P. Mackay, Amy I. Smith-Dijak, Ellen T. Koch, Peng Zhang, Evan Fung, Wissam B. Nassrallah, Caodu Buren, Mandi Schmidt, Michael R. Hayden, Lynn A. Raymond
Summary: Miniature neurotransmission is increased in the Huntington disease (HD) model, associated with abnormal endoplasmic reticulum (ER) calcium handling. These abnormalities influence neurotransmission indirectly, without direct ER calcium release into the cytoplasm. However, in cortical cultures and brain slices, there are no significant differences in calcium release between the HD-model neurons and wild-type cells.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Clinical Neurology
Borje Darpo, Michal Geva, Georg Ferber, Yigal Paul Goldberg, Andres Cruz-Herranz, Munish Mehra, Richard Kovacs, Michael R. Hayden
Summary: Pridopidine, a selective sigma-1 receptor agonist, shows a favorable cardiac safety profile at the therapeutic dose of 45 mg bid, with no clinically relevant effect on the QT interval.
NEUROLOGY AND THERAPY
(2023)
Article
Clinical Neurology
Andreas-Antonios Roussakis, Marta Gennaro, Mark Forrest Gordon, Ralf Reilmann, Beth Borowsky, Gail Rynkowski, Nicholas P. Lao-Kaim, Zoe Papoutsou, Juha-Matti Savola, Michael R. Hayden, David R. Owen, Nicola Kalk, Anne Lingford-Hughes, Roger N. Gunn, Graham Searle, Sarah J. Tabrizi, Paola Piccini
Summary: This longitudinal study demonstrates that the treatment of laquinimod in Huntington's disease does not affect regional microglia activation. Microglia activation is believed to be related to inflammation in the central nervous system and the progression of Huntington's disease. However, laquinimod is capable of regulating microglia. The study also shows that C-11-PBR28 PET-CT imaging can be used to assess regional gliosis and the effects of laquinimod treatment.
BRAIN COMMUNICATIONS
(2023)
Article
Biotechnology & Applied Microbiology
Neel Mehta, Renald Gilbert, Parminder S. Chahal, Maria J. Moreno, Nasha Nassoury, Nathalie Coulombe, Viktoria Lytvyn, Mario Mercier, Dorothy Fatehi, Wendy Lin, Emily M. Harvey, Lin-Hua Zhang, Nazila Nazemi-Moghaddam, Seyyed Mehdy Elahi, Colin J. D. Ross, Danica B. Stanimirovic, Michael R. Hayden
Summary: This study aimed to develop a more efficacious AAV gene therapy vector for the treatment of LPLD. The researchers identified AAV8 pVR59 as a superior vector compared to AAV1 (Glybera), with significantly better therapeutic effects at lower doses. AAV8 pVR59 treatment led to long-term correction of LPLD and improvement in pathology.
HUMAN GENE THERAPY
(2023)
Article
Biotechnology & Applied Microbiology
Fabio Duarte, Gabriel Vachey, Nicholas S. Caron, Melanie Sipion, Maria Rey, Anselme L. Perrier, Michael R. Hayden, Nicole Deglon
Summary: Huntington's disease is a fatal neurodegenerative disorder that can be treated by inactivating the mutated HTT gene. One approach to selectively inactivate the mutant allele is by using the CRISPR/Cas9 system to remove the first exon of the mutated HTT. However, the frequency of deletion events is still uncertain.
HUMAN GENE THERAPY
(2023)