The novel protein mesencephalic astrocyte-derived neurotrophic factor (MANF) is a survival molecule (alternatively referred to as arginine-rich, mutated in early stage tumors, or ARMET) that has high selectivity for dopaminergic neurons of the midbrain^1,2. There, it induces proliferative and protective effects against neurodegeneration (usually caused by 6-hydroxydopamine); its therapeutic potential in dopamine-related neurodegenerative disorders such as Parkinson's disease is therefore promising^3,4.

MANF is also expressed cardiac tissues. As was recently suggested, it induces cardioprotection in the heart and anti-hypertrophic effects via reducing endoplasmic reticulum stress in ischemic conditions in both the heart and the brain. Thus, its effects stretch beyond rescue and protection of dopaminergic neurons alone^1,5.

Generally, neurotrophic factors (NTFs) provide support, protection, and regulation for neurons – with each group of neurons having their own unique NTFs – both during development and at adulthood. Other noticeable NTFs include neurotrophin-3 and -4 (NT3 and NT4), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and glial cell derived neurotrophic factor (GDNF)⁶.

MANF is considered to be evolutionary conserved within Mammalia and beyond (including distant species such as nematode and fruit fly – the latter shares more than 50% identity with human MANF gene) and is highly mutative in many tumors. It is mostly composed of alpha helices and random coils; its structure essentially differs from any other neurotrophic factor. It is suggested that the protein initiates intracellular signaling cascade by binding to cell-surface lipids and membranes via its cysteine-rich N-terminal. Together with its C-terminal which contains a disulfide bridge that endows a cytoprotective response against ER stress, MANF is implied to be bi-functional^3,7.