Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although tradi Show more
Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). Show less
Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parki Show more
Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration. Show less