Research in the Weiss lab is directed toward understanding the molecular and cellular mechanisms underlying human diseases caused by dysfunction of ion channels, and more especially calcium channels. Calcium is Mother Nature’s “ion-of-choice” for orchestrating fundamental cellular functions, as it contribute to neuronal excitability, muscle contraction, gene transcription, and a plethora of other key processes contributing to the normal physiology of the body. Calcium channels, which act as gated pathways for the movement of calcium across the cell membranes, play a central part in the initiation of the calcium signals, and defects in calcium channel function have dramatic consequences resulting in sever human diseases, so-called channelopathies.
Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system, the cardiovascular system , the respiratory system, the endocrine system, the urinary system, and the immune system. There are two types of channelopathies: congenital and acquired. Congenital conditions are genetic in nature and can be inherited or the result of spontaneous mutations. Acquired conditions occur usually later in life and are the result of alteration of ion channels functions caused by aging, drugs, toxins and other cellular environment.
Major themes of the Weiss lab
Our research is centered on the molecular and physiological intrinsic and extrinsic factors that control the functioning of neuronal calcium channels and ultimately the excitability and communication between nerve cells. This focus integrates three major themes: First, we aim to dissect the molecular machinery controlling the physiological trafficking of neuronal calcium channels to the plasma membrane, and how metabolic defects associated with a number of chronic disorders such as type 2 diabetes hijack this machinery eventually leading to neuronal pathologies such as epilepsy or neuropathic pain. Second, we aim to analyze the functional consequence of genetic mutations in the calcium channel itself, or in the trafficking machinery units, providing a genetic-functional link to inherited neuronal disorders. Ultimately, we wish to translate new insights into the development of novel therapeutic avenues.
See below for more information on our current projects.
Glycosylation of T-type calcium channels in health and disease
The cellular and physiological functions supported by ion channels are not only determine by the intrinsic functional properties of the channels embedded in the plasma membrane but also by the number of channels that are expressed at the cell surface, their dynamic (stability) and more importantly by their specific expression in subcellular loci. Protein glycosylation is rapidly emerging as a fundamental post-translational mechanism controlling those aspects, and defects in ion channel glycosylation give rise to numerous human disorders. For instance, alteration of T-type calcium channel expression during diabetes has been documented and is believed to be one of the underlying factors responsible for painful diabetic neuropathy. We are exploring the role of glycosylation in the sorting and trafficking of T-type calcium channels to better understand their molecular dynamic in normal and pathological conditions.