Exploring presenilin-1-associated familial Alzheimer's disease

Familial Alzheimer's disease (FAD) is an early on-set, hereditary form of neurological disease with variable pathophysiology that is often associated with loss of cerebellar function and amyloid plaque formation. Diego Sepulveda-Falla and colleagues investigated how a particular PS1 mutation (PS1-E280A), present in large Columbian kindred of FAD patients, promotes disease. Postmortem evaluation of cerebellar tissue from patients revealed that PS1-E280A is associated with Purkinje cell loss, an abundance of abnormal mitochondria and loss of calcium transport proteins. Furthermore, cell culture and murine models of PS1-E280A FAD revealed that PS1alterations disrupt calcium homeostasis and mitochondrial transport within cerebellar neurons, resulting in increased amyloid plaque formation and cerebellar dysfunction.

Prenatal environment influences the adult airway

Vitamin A and its active metabolite retinoic acid (RA) are essential for lung formation, though it is not clear if prenatal vitamin A deficiency influences postnatal lung development and function. In this episode, Wellington Cardoso provides evidence that prenatal disruption of RA signaling results in aberrant, overly differentiated smooth muscle in airways. RA deficiency-associated defects persisted, regardless of the adult vitamin A status, and manifested in airway hyperresponsiveness and structural changes in the bronchial smooth muscle. The study indicates that RA signaling in the developing lung prevents excessive smooth muscle formation.

A pharmacological approach to reversing aniridia

Nonsense mutations that lead to PAX6 haploinsufficiency cause congenital aniridia, a panocular condition that results in severe vision defects. Cheryl Gregory-Evans and colleagues hypothesized that suppression of nonsense mutations could increase PAX6 levels and prevent post-natal eye damage. They developed a topical formulation of ataluren that not only inhibited disease progression, but also reversed ocular malformations and restored retinal responses in Pax6-deficient mice.

Maintaining T cell polyfunctionality

In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.

Protecting the kidney through ion channel inhibition

Damage to the glomerulus, which mediates the kidney's filtering function, causes plasma protein to spill into the urine, a sign of kidney failure and cardiovascular disease. Calcium influx into the podocytes, the cells that form the filtration barrier of the glomerulus, is known to damage the glomerulus, but the ion channel that mediates this influx was unknown. In this episode, Anna Greka and colleagues discuss their recent work demonstrating that inhibition of the TRPC5 ion channel protects mice from kidney damage by preventing calcium influx into the podocytes, and blocks the cytoskeletal alterations in the podocytes that disrupts the filtration barrier in the glomerulus.