Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS
The hPFN1G118V mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral,...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001913 |
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| author | Kaly A. Mueller Emma G. Suneby Matthew H. Ferola Andy J. Moreno Joshua D. Kidd Kenneth Thompson Fernando G. Vieira Gregorio Valdez Theo Hatzipetros |
| author_facet | Kaly A. Mueller Emma G. Suneby Matthew H. Ferola Andy J. Moreno Joshua D. Kidd Kenneth Thompson Fernando G. Vieira Gregorio Valdez Theo Hatzipetros |
| author_sort | Kaly A. Mueller |
| collection | DOAJ |
| description | The hPFN1G118V mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1G118V mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts. |
| format | Article |
| id | doaj-art-6a446deac8d74b478229bbeb158d00df |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-6a446deac8d74b478229bbeb158d00df2025-08-20T02:05:11ZengElsevierNeurobiology of Disease1095-953X2025-08-0121210697510.1016/j.nbd.2025.106975Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALSKaly A. Mueller0Emma G. Suneby1Matthew H. Ferola2Andy J. Moreno3Joshua D. Kidd4Kenneth Thompson5Fernando G. Vieira6Gregorio Valdez7Theo Hatzipetros8ALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USADepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship St, Providence, RI, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USADepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship St, Providence, RI, USAALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA, USA; Corresponding author at: ALS Therapy Development Institute, 480 Arsenal Street, Watertown, MA 02472, USA.The hPFN1G118V mouse model, overexpressing mutant human profilin1 linked to a rare form of ALS, was comprehensively characterized to assess its suitability for preclinical drug testing. Using a large cohort of nearly 250 transgenic and wild-type mice in a longitudinal study, we combined behavioral, electrophysiological, and neuropathological assessments to define the chronology of pathological events and assess inherent subject variability. The early stage of the disease in this model was characterized by elevated plasma neurofilament light chain levels, an effect that persisted and progressed throughout the course of the disease, followed by spinal cord neuroinflammation, suggesting that axonal pathology is the initiating event. The middle stage of the disease involved progressive neuromuscular decline, including reductions in compound muscle action potential (CMAP) and grip strength, accompanied by neuromuscular junction degeneration. The end-stage of the disease was characterized by the onset of visible changes such as weight loss, gait abnormalities and hindlimb paresis that quickly progressed to paralysis. At end-stage we also observed spinal motor neuron loss and TDP-43 pathology. The average humane endpoint was 213 days for females and 237 days for males. Our findings demonstrate that hPFN1G118V mice recapitulate key ALS features with moderate disease progression and a reproducible disease course, making them a valuable model for therapeutic testing. Recommendations are provided to optimize study design for preclinical testing, emphasizing survival duration as the primary endpoint, with CMAP and plasma NFL as key secondary readouts.http://www.sciencedirect.com/science/article/pii/S0969996125001913Amyotrophic lateral sclerosisProfilin1Motor neuronsNeurofilament light chainCMAPNeuroinflammation |
| spellingShingle | Kaly A. Mueller Emma G. Suneby Matthew H. Ferola Andy J. Moreno Joshua D. Kidd Kenneth Thompson Fernando G. Vieira Gregorio Valdez Theo Hatzipetros Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS Neurobiology of Disease Amyotrophic lateral sclerosis Profilin1 Motor neurons Neurofilament light chain CMAP Neuroinflammation |
| title | Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS |
| title_full | Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS |
| title_fullStr | Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS |
| title_full_unstemmed | Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS |
| title_short | Comprehensive characterization and validation of the Prp-hPFN1G118V mouse model: Guidelines for preclinical therapeutic testing for ALS |
| title_sort | comprehensive characterization and validation of the prp hpfn1g118v mouse model guidelines for preclinical therapeutic testing for als |
| topic | Amyotrophic lateral sclerosis Profilin1 Motor neurons Neurofilament light chain CMAP Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125001913 |
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