Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice

Area of Science:

• Neuroscience
• Molecular Biology
• Protein Dynamics

Background:

• Molecular chaperones, like heat shock protein 27 (Hsp27), are crucial for regulating protein aggregation implicated in neurodegenerative diseases.
• Translating findings from protein aggregation models to the mammalian brain remains a challenge.

Purpose of the Study:

• To investigate the role of Hsp27 in modulating tau protein dynamics in a mouse model of tauopathy.
• To compare the effects of wild-type Hsp27 and a constitutively pseudo-phosphorylated mutant (3×S/D Hsp27) on tau aggregation and neuronal function.

Main Methods:

• Generated recombinant wild-type Hsp27 and 3×S/D Hsp27.
• Utilized atomic force microscopy and dynamic light scattering to assess tau filament formation.
• Employed adeno-associated viral vectors for genetic delivery of Hsp27 variants to tau transgenic mice.
• Measured neuronal tau levels and hippocampal long-term potentiation (LTP) to evaluate Hsp27 efficacy.

Main Results:

• Both Hsp27 variants interacted with tau and inhibited filament formation in vitro.
• In vivo, wild-type Hsp27 reduced neuronal tau levels, while 3×S/D Hsp27 increased them.
• Wild-type Hsp27 rescued the decay in LTP, whereas the 3×S/D mutant did not.

Conclusions:

• Hsp27's functional dynamism, specifically its phosphorylation cycle, is essential for facilitating tau clearance and rescuing cognitive deficits.
• Compromised Hsp27 dynamism may lead to the accumulation of soluble tau intermediates, potentially exacerbating disease pathology.
• These findings highlight the importance of Hsp27's dynamic state in therapeutic strategies for tauopathies.