Article
Biochemistry & Molecular Biology
Hiroyuki Yabata, Yuichi Riku, Hiroaki Miyahara, Akio Akagi, Jun Sone, Makoto Urushitani, Mari Yoshida, Yasushi Iwasaki
Summary: The study aimed to evaluate the relationship between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in ALS cases. The results showed that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This suggests that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Marcus S. Dyer, G. Lorenzo Odierna, Rosemary M. Clark, Adele Woodhouse, Catherine A. Blizzard
Summary: This study investigates the relationship between cortical hyperexcitability and altered synaptic input in amyotrophic lateral sclerosis (ALS) using a mouse model. The findings suggest that intrinsic hyperexcitability precedes changes to excitatory synaptic connections, highlighting the significance of hyperexcitability as a primary mechanism of ALS and re-contextualizing synaptic changes as secondary adaptive responses.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Clinical Neurology
Abrar Alhindi, Megan Shand, Hannah L. Smith, Ana S. Leite, Yu-Ting Huang, Dinja van Der Hoorn, Zara Ridgway, Kiterie M. E. Faller, Ross A. Jones, Thomas H. Gillingwater, Helena Chaytow
Summary: This study comprehensively analyzed the neuromuscular junction pathology in a mouse model of ALS. The results showed progressive, region-specific motor neuron pathology in Thy1-hTDP-43(WT) mice. The loss of terminal Schwann cells was directly correlated with motor neuron denervation.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2023)
Article
Neurosciences
Megan Dubowsky, Frances Theunissen, Jillian M. Carr, Mary-Louise Rogers
Summary: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder characterized by the death of upper and lower motor neurons. It is proposed that endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), play a role in the propagation of neurodegeneration in ALS. This review discusses the involvement of transactive response DNA binding protein 43 kDa (TDP-43), HERV-K, and immune regulators in the onset and progression of ALS, as well as the potential of targeting ERVs as a therapy for ALS.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sean S. Keating, Adekunle T. Bademosi, Rebecca San Gil, Adam K. Walker
Summary: Aggregation of TDP-43 is the hallmark of neurodegenerative diseases, involving depletion, mislocalisation, and post-translational modification of normal nuclear TDP-43. Oxidative stress triggers liquid-liquid phase separation of TDP-43, while RNA-binding deficiency and acetylation mimicry lead to sequestration of normal nuclear TDP-43 into dynamic anisosomes. Nuclear or cytoplasmic aggregation-prone TDP-43 mutants form phosphorylated inclusions that immobilize and insolubilize endogenous TDP-43, indicating pathological transition. Overall, these findings highlight the importance of RNA-binding deficiency and post-translational modifications in driving TDP-43 aggregation and dysfunction in neurodegenerative diseases.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Clinical Neurology
Hadjara Sidibe, Yousra Khalfallah, Shangxi Xiao, Nicolas B. Gomez, Hana Fakim, Elizabeth M. H. Tank, Genevieve Di Tomasso, Eric Bareke, Anais Aulas, Paul M. McKeever, Ze'ev Melamed, Laurie Destroimaisons, Jade-Emmanuelle Deshaies, Lorne Zinman, J. Alex Parker, Pascale Legault, Martine Tetreault, Sami J. Barmada, Janice Robertson, Christine Vande Velde
Summary: The study reveals that TDP-43 stabilizes G3BP1 transcripts, nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels, and G3BP1 transcripts are reduced in neurons of ALS/FTD patients with TDP-43 cytoplasmic inclusions/nuclear depletion. These findings suggest that loss of function of TDP-43 and G3BP1 may contribute to ALS/FTD pathogenesis.
Article
Biochemistry & Molecular Biology
Giada Zanini, Valentina Selleri, Milena Nasi, Anna De Gaetano, Ilaria Martinelli, Giulia Gianferrari, Francesco Demetrio Lofaro, Federica Boraldi, Jessica Mandrioli, Marcello Pinti
Summary: This study reports the clinical and biological features of an ALS patient with pA382T mutation in TPD-43 protein. The mutation leads to significant alterations in neuronal proteome, particularly impacting mitochondrial metabolic pathways and the endoplasmic reticulum. The findings suggest that mitochondrial dysfunction and misplacement of mitochondrial DNA may be mechanisms contributing to ALS caused by this mutation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Nirma D. Perera, Doris Tomas, Nayomi Wanniarachchillage, Brittany Cuic, Sophia J. Luikinga, Valeria Rytova, Bradley J. Turner
Summary: Autophagy plays a crucial role in maintaining cell homeostasis, but excessive induction may accelerate neurodegenerative diseases. This study demonstrated that stimulating autophagy with rilmenidine exacerbated the ALS phenotype in a TDP-43 mouse model, likely through excessive mitochondrial clearance in motor neurons. Balancing autophagy stimulation and hyperactive mitophagy is essential in ALS and other neurodegenerative diseases.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Clinical Neurology
Alessio Maranzano, Barbara Poletti, Federica Solca, Silvia Torre, Eleonora Colombo, Matteo Fare, Roberta Ferrucci, Laura Carelli, Federico Verde, Claudia Morelli, Vincenzo Silani, Nicola Ticozzi
Summary: This study found that the burden of upper motor neuron involvement is associated with the presence of behavioral impairment in ALS patients, suggesting a preferential spreading of pathology from the motor cortex to the ventromedial prefrontal and orbitofrontal cortex.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Article
Neurosciences
Mukesh Gautam, Baris Genc, Benjamin Helmold, Angela Ahrens, Janis Kuka, Marina Makrecka-Kuka, Aksu Gunay, Nuran Kocak, Izaak R. Aguilar-Wickings, Dennis Keefe, Guozhu Zheng, Suchitra Swaminathan, Martin Redmon, Hatim A. Zariwala, P. Hande Ozdinler
Summary: Mitochondrial defects are a common cause of neuronal vulnerability in neurodegenerative diseases, and TDP-43 pathology is frequently observed. By using a mouse model of ALS, researchers found that SBT-272, a small molecule that stabilizes cardiolipin in the inner mitochondrial membrane, improved mitochondrial structure and function in diseased upper motor neurons. Chronic treatment with SBT-272 also reduced astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. These findings highlight the therapeutic potential of SBT-272 in the context of TDP-43 pathology and mitochondrial dysfunction.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Clinical Neurology
Yuting Ren, Siyuan Li, Siyu Chen, Xiaosun Sun, Fei Yang, Hongfen Wang, Mao Li, Fang Cui, Xusheng Huang
Summary: The levels of plasma TDP-43 and pTDP-43 were significantly higher in ALS patients compared to healthy controls, with plasma TDP-43 showing high sensitivity and specificity in differentiating between the two groups and indicating disease progression.
FRONTIERS IN NEUROLOGY
(2021)
Review
Pharmacology & Pharmacy
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc'h, Philippe Corcia, Debora Lanznaster, Helene Blasco
Summary: ALS is a fatal neurodegenerative disease without effective treatment. TDP-43, a major therapeutic target in ALS, has been studied for its cellular functions and pathological effects. Various pathways have been explored for mitigating TDP-43 pathology in ALS.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)
Article
Biochemistry & Molecular Biology
Han-Cheon Kim, Yan Zhang, Peter H. H. King, Liang Lu
Summary: ALS is a fatal neurodegenerative disease characterized by motor neuron damage and TDP-43 proteinopathy. This study shows that miR-183-5p is aberrantly upregulated in ALS patients and regulates TDP-43 protein levels through the SQSTM1/p62 pathway. It provides a novel mechanism linking abnormal RNA processing and protein degradation in ALS pathogenesis.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Geriatrics & Gerontology
Zhe Long, Muireann Irish, John R. Hodges, Glenda Halliday, Olivier Piguet, James R. Burrell
Summary: Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. Characteristics that differentiate between FTLD-TDP and FTLD-tau, as well as different subtypes within FTLD-TDP, were investigated. Amyotrophic lateral sclerosis features were highly specific for FTLD-TDP, which showed greater atrophy than FTLD-tau. TDP-43 subtyping may have more clinical utility in distinguishing different profiles within FTLD-TDP.
NEUROBIOLOGY OF AGING
(2021)
Article
Cell Biology
Sonali S. Vishal, Denethi Wijegunawardana, Muthu Raj Salaikumaran, Pallavi P. Gopal
Summary: This study identifies key structural elements, including the alpha-helical domain, phenylalanine residues within the LARKS, and the RGG motif, that are crucial for TDP-43 RNP transport and condensate formation in neurons. These findings suggest that these structural elements may mediate efficient recruitment of motors and adaptor proteins, and offer a possible mechanism underlying ALS-linked TDP-43 defects in axonal transport and homeostasis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)