Question

Cyst formation causes a catastrophic loss of function in polycystic kidney disease.  Genetic research has linked this disease to defects in genes that code for primary cilium proteins.  Describe in general terms how malfunctioning primary cilia cause the formation of kidney cysts.

Answer 1

Primary cilia are specialized organelles present on most cell types. Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia. Abnormal cilia structure and/or function have been reported in animal models and human cystic kidneys.Novel direct recording of cilia calcium level/channel activity suggest that cilia form a calcium-mediated signaling microenvironment separate from the cytoplasm, which could provide a mechanism for cilia-specific downstream signaling. Genetic-based studies confirm that cilia are not required for cystogenesis but modulate cystic kidney disease severity through a novel, undefined mechanism. Mechanisms by which both cilia-associated and non-cilia associated proteins can alter cilia structure/function have also been identified.

Considerable progress has been made in defining the mechanisms by which abnormal genes and proteins affect cilia structure and function. However, the exact mechanisms by which these interactions cause renal cyst formation and progression of cystic kidney disease are still unknown.Although many ciliopathies demonstrate abnormal or absent cilia, cilia are not required for cyst formation. The presence of intact cilia may, promote worsening cystic kidney disease in the presence of abnormal PKD proteins. New mechanisms whereby non-cilia associated proteins impact cilia structure and function have been identified.The interactions of diverse cilia-associated cystic kidney disease proteins continue to be investigated, with an expanding list of proteins that comprise the polycystin cilia signaling complex .

• Cilia are complex organelles present on most cell types in the body, including renal epithelial cells and participate in processes that may contribute to cyst formation such as flow-mediated intracellular calcium release.
• Proteins from nearly all of the human cystic kidney diseases have been localized to the cilium or basal body, and abnormalities in cilia structure and/or function are common features of the ciliopathies.
• cilia form a distinct calcium-mediated signaling microenvironment separate from the cytoplasm, are capable of modulating the severity of PKD, and their structure or function may be modulated by both cilia-associated and non-cilia associated proteins.

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