Chaperones increase association of tau protein with microtubules

Abstract

Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, includingParkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., ␣-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by ␤-amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)70͞90 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

“…This function is accomplished due to the proteins' intracellular chaperone activity and is responsible for the refolding of stressdenatured proteins and stabilization of transcription and translation (Lindquist and Craig 1988;Morimoto 1991;De Maio 1999). More recently, it has been shown that hsp also regulate other cellular activities such as cytoskeleton rearrangement (Han et al 2000;Kirby et al 1994;Liao et al 1995;Dou et al 2003;Lavoie et al 1993;Piotrowicz and Levin 1997), endocytosis and phagocytosis (Vega et al 2010;Vega and De Maio 2005), and activation of immune cells (Vega et al 2008;Asea et al 2000Asea et al , 2002. Especially interesting is the capacity of both extra-and intracellular hsp to regulate the immune system by activation of key cells such as macrophages (Mfs) and dendritic cells, thereby controlling inflammatory and immune responses (Vega et al 2010;De Maio 2010;Asea et al 2000Asea et al , 2002Basu et al 2001).…”

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

“…The ability to co-express gene products with the vector system permits screening gene targets that can either intensify tau pathology or block it. For example, chaperone co-factors such as Hsp70 can regulate tau processing (Dou et al, 2003;Petrucelli et al, 2004). If a specific gene product efficaciously blocks tau toxicity in rats, it could be pursued as a gene therapy for tauopathies, especially genetically determined tauopathies such as FTDP-17, because there are no treatments currently available for this fatal condition.…”

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

“…35 Cells were lysed in a buffer containing 0.5% Nonidet P-40, 1 mM EDTA, 50 mM Tris-HCl, pH 8.0, 120 mM NaCl, and a protease inhibitor mixture. After brief sonication, cell lysates were passed through a cellulose acetate membrane (0.2 mm; Bio-Rad) using a Bio-Dot Microfiltration Apparatus (Bio-Rad) and were washed for 15 min (three times) with 1% SDS followed by immunoblotting using Tau5 antibody.…”