The neurotoxin β-N-methylamino-L-alanine (BMAA) produced by marine diatoms has been implicated as an important environmental trigger of neurodegenerative diseases in humans. However, the biosynthesis mechanism of BMAA in marine diatoms is still unknown. In the present study, the strain of diatom Thalassiosira minima almost lost the biosynthesis ability for BMAA after a long-term subculture in our laboratory. The production of BMAA-containing proteins in the mutant strain of T. minima reduced to 18.2% of that in the wild strain, meanwhile the cell size decreased but pigment content increased in the mutant strain. Take consideration of our previous transcriptional data on the mixed diatom and cyanobacterium cultures, the current transcriptome analysis showed four identical and highly correlated KEGG pathways associated with the accumulation of misfolded proteins in diatom, including ribosome, proteasome, SNARE interactions in vesicle transport, and protein processing in the endoplasmic reticulum. Analysis of amino acids and transcriptional information suggested that amino acid synthesis and degradation are associated with the biosynthesis of BMAA-containing proteins. In addition, a reduction in the precision of ubiquitination-mediated protein hydrolysis and vesicular transport by the COPII system will exacerbate the accumulation of BMAA-containing proteins in diatoms. Environmental ImplicationWith the detection of neurotoxin BMAA from diverse marine diatoms, the environmental risk of BMAA has been further strengthened to human neurodegenerative diseases such as Alzheimer’s disease. It is a keystone issue to disclose the biosynthesis mechanism of BMAA in marine diatoms. One strain of Thalassiosira minima almost lost the production ability of BMAA after a long period of subculture due to mutation. In this study, pigment composition, photosynthetic parameters and transcriptional expression were analyzed and compared between the mutated strain and its original wild strain to elucidate possible molecular mechanisms of BMAA biosynthesis.