CD4+ T cells respond to buildups of alpha-synuclein, a Northwestern Medicine study has found. Alpha-synuclein are a feature of neurodegenerative diseases including dementia with Lewy bodies (LWD) and Parkinson’s disease (PD).
This autoimmune response proves harmful, and inhibiting signaling pathways that trigger the response may represent a future therapeutic target, according to David Gate, Ph.D., assistant professor of Neurology and lead author of the study1.
These findings have established a detrimental role of the immune system in Lewy body dementias,
CX-C Motif Chemokine Receptor 4
Investigators analyzed cerebrospinal fluid (CSF) from patients with LBD and compared that to fluid from healthy aged controls. In patients with LBD, study authors discovered upregulated expression of CX-C Motif Chemokine Receptor 4 (CXCR4), a protein that normally regulates directing immune cells to tissues.
It can be thought of as an antenna on the cell’s surface that receives signals from a cytokine called CXCL12,
Patients with LBD have an increased level of CXCL12, likely caused by alpha-synuclein. This leads T-cells to respond to the alpha-synuclein, secreting a toxic molecule called interleukin-17 which can damage neurons.
Intracellular clumps of debris — misfolded proteins, damaged lipids and pieces of partly digested organelles — are one of the hallmarks of Lewy body dementias. One major component of these clumps — the eponymous Lewy bodies — is the misfolded protein alpha-synuclein.
There are already drugs that inhibit CXCR4 and are used to treat blood cancers and HIV2, and these could be used to interrupt this auto-immune response, according to Gate. These drugs could be repurposed to inhibit pathological T-cell entry into the LBD brain, Gate speculated.
Further, measuring levels of CXCL12 in CSF could be used to estimate how much autoimmune activity a patient with LBD is experiencing, as levels of CXCL12 correlate with levels of neurofilaments3, proteins that are released by neurons when they are injured or die.
David Gate et al. CD4 + T cells contribute to neurodegeneration in Lewy body dementia. Science (2021). DOI: 10.1126/science.abf7266 ↩︎
Y. Iwasaki, H. Akari, T. Murakami, S. Kumakura, M. Z. Dewan, M. Yanaka, N. Yamamoto. Efficient inhibition of SDF-1alpha-mediated chemotaxis and HIV-1 infection by novel CXCR4 antagonists. Cancer Sci. 100, 778–781 (2009). ↩︎
Khalil, M. et al. Neurofilaments as biomarkers in neurological disorders. Nat. Rev. Neurol. 14, 577–589 (2018). ↩︎