Targeting anaplastic lymphoma kinase (ALK) alleviates synaptic dysfunction associated with C9orf72 haploinsufficiency

Topic: Brain proteins, microglia and lab models

Primary cortical neurons with C9orf72 haploinsufficiency exhibit alterations in dendritic branching, indicating disrupted neuronal connectivity. Additionally, C9orf72 haploinsufficiency increases neuronal vulnerability to excitotoxicity and cell death under stress, evidenced by reduced viability following high glutamate exposure. Glutamate excitotoxicity is a common pathomechanism in neurodegenerative diseases, including FTD/ALS. This can be explained by elevated calcium-permeable AMPAR subunit GluA1 levels at post-synaptic sites, increasing vulnerability. These synaptic dysfunction phenotypes arise from aberrant activity of interrelated PI3K/Akt and LIMK1/cofilin pathways. Importantly, inhibition of ALK by lorlatinib rescues dendritic complexity and enhances neuronal resilience to glutamate-induced damage by normalizing PI3K/Akt and LIMK1/cofilin activity. Lorlatinib may mitigate synaptic dysfunction and preserve neuronal connectivity, addressing key pathomechanisms underlying C9orf72-FTD. Our findings highlight the therapeutic potential of lorlatinib, an ALK inhibitor, in mitigating synaptic deficits caused by C9orf72 haploinsufficiency. We emphasize the role of synaptic pathology in C9orf72-FTD pathogenesis and suggest that targeting ALK with drugs like lorlatinib could offer promising therapeutic strategies for treating synaptic dysfunction caused by C9orf72 haploinsufficiency.

Key findings

• Primary cortical neurons with C9orf72 haploinsufficiency exhibit alterations in dendritic branching, indicating disrupted neuronal connectivity.
• Additionally, C9orf72 haploinsufficiency increases neuronal vulnerability to excitotoxicity and cell death under stress, evidenced by reduced viability following high glutamate exposure.
• Glutamate excitotoxicity is a common pathomechanism in neurodegenerative diseases, including FTD/ALS.
• This can be explained by elevated calcium-permeable AMPAR subunit GluA1 levels at post-synaptic sites, increasing vulnerability.
• These synaptic dysfunction phenotypes arise from aberrant activity of interrelated PI3K/Akt and LIMK1/cofilin pathways.

Why it matters

In cultured neurons with C9orf72 haploinsufficiency, the ALK inhibitor lorlatinib rescued dendritic complexity and improved resilience to glutamate-induced damage. These are cell-based findings related to C9orf72-FTD, not evidence of treating, curing or preventing Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70855_099957
• PubMed: 41436064
• Original source →
• Free full text: Alzheimer s & Dementia →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{kartono2025-41436064,
  author  = {Kartono, Bryan and Attisano, Liliana and Robertson, Janice},
  title   = {{Targeting anaplastic lymphoma kinase (ALK) alleviates synaptic dysfunction associated with C9orf72 haploinsufficiency}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70855_099957},
  pmid    = {41436064},
  url     = {https://doi.org/10.1002/alz70855_099957}
}

Related studies in Disease mechanisms

• Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis Cerebellum (London, England) · 2021-09-07 · usefulness score 50/100
• c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo Cell death & disease · 2014-01-23 · usefulness score 40/100
• Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer's Disease Molecular neurobiology · 2016-10-13 · usefulness score 39/100
• Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination Journal of Alzheimer's disease : JAD · 2014 · usefulness score 38/100
• C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo Nature neuroscience · 2019-05-13 · usefulness score 41/100
• Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer's disease Aging cell · 2020-05-17 · usefulness score 41/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Saikosaponin C ameliorates tau-related pathology by modulating oxidative stress and MAPK axis in Alzheimer's disease Journal of Ethnopharmacology · 2025-07-02 · usefulness score 42/100 · Disease mechanisms
• A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells The Journal of experimental medicine · 2001-10-01 · usefulness score 52/100 · TREM2 and immune genetics
• Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice Frontiers in molecular neuroscience · 2017-05-19 · usefulness score 48/100 · Inflammation and the immune system

Similar studies

• Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease 2017 · Disease mechanisms
• Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases 2025 · Lewy body dementia
• c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model 2011 · Disease mechanisms
• Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death 2016 · Lewy body dementia
• Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation 2018 · Inflammation and the immune system
• Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs 2016 · Lewy body dementia

More on Disease mechanisms

• A review that covers this ground Targeting Synaptic Plasticity in Experimental Models of Alzheimer's Disease Frontiers in pharmacology · 2019-07-16 · usefulness score 39/100
• Newest in this subject Aβ42 oligomers disrupt calcium homeostasis via Piezo1 and induce neurotoxicity in differentiated SH-SY5Y cells Research Square · 2026-10-29 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation bioRxiv · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Disease mechanisms →